245 results on '"Lathia JD"'
Search Results
2. Sex-dependent niche responses modulate steady-state and regenerative hematopoiesis.
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Chaudhary R, Smith JNP, Tiwari R, Klein BR, Cordova BA, Petroze F, Richardson B, Broncano AV, Lee J, Parthasarathy PB, De Carvalho KIL, Cameron SJ, Lathia JD, Goodman WA, Cameron MJ, and Desai AB
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- Animals, Male, Female, Mice, Stem Cell Niche, Sex Characteristics, Hematopoietic Stem Cells metabolism, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cell Transplantation, Regeneration, Mice, Inbred C57BL, Transcriptome, Chemokine CXCL12 metabolism, Chemokine CXCL12 genetics, Hematopoiesis
- Abstract
Hematopoietic stem cells (HSCs) adapt to organismal blood production needs by balancing self-renewal and differentiation, adjusting to physiological demands and external stimuli. Although sex differences have been implicated in differential hematopoietic function in males versus females, the mediators responsible for these effects require further study. Here, we characterized hematopoiesis at a steady state and during regeneration following hematopoietic stem cell transplantation (HST). RNA sequencing of lineage(-) bone marrow cells from C57/Bl6 mice revealed a broad transcriptional similarity between the sexes. However, we identified distinct sex differences in key biological pathways, with female cells showing reduced expression of signatures involved in inflammation and enrichment of genes related to glycolysis, hypoxia, and cell cycle regulation, suggesting a more quiescent and less inflammatory profile compared with male cells. To determine the functional impacts of the observed transcriptomic differences, we performed sex-matched and mismatched transplantation studies of lineage(-) donor cells. During short-term 56-day HST recovery, we found a male donor cell proliferative advantage, coinciding with elevated serum TNF-α, and a male recipient engraftment advantage, coinciding with increased serum CXCL12. Together, we show that sex-specific cell responses, marked by differing expression of pathways regulating metabolism, hypoxia, and inflammation, shape normal and regenerative hematopoiesis, with implications for the clinical understanding of hematopoietic function., Competing Interests: Conflict of Interest Disclosure The authors have no conflicts of interest to declare., (Copyright © 2024 International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)
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- 2024
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3. Sexually dimorphic computational histopathological signatures prognostic of overall survival in high-grade gliomas via deep learning.
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Verma R, Alban TJ, Parthasarathy P, Mokhtari M, Toro Castano P, Cohen ML, Lathia JD, Ahluwalia M, and Tiwari P
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- Humans, Female, Male, Prognosis, Middle Aged, Neoplasm Grading, Adult, Aged, Glioma pathology, Glioma mortality, Deep Learning, Brain Neoplasms pathology, Brain Neoplasms mortality, Sex Characteristics, Tumor Microenvironment
- Abstract
High-grade glioma (HGG) is an aggressive brain tumor. Sex is an important factor that differentially affects survival outcomes in HGG. We used an end-to-end deep learning approach on hematoxylin and eosin (H&E) scans to (i) identify sex-specific histopathological attributes of the tumor microenvironment (TME), and (ii) create sex-specific risk profiles to prognosticate overall survival. Surgically resected H&E-stained tissue slides were analyzed in a two-stage approach using ResNet18 deep learning models, first, to segment the viable tumor regions and second, to build sex-specific prognostic models for prediction of overall survival. Our mResNet-Cox model yielded C-index (0.696, 0.736, 0.731, and 0.729) for the female cohort and C-index (0.729, 0.738, 0.724, and 0.696) for the male cohort across training and three independent validation cohorts, respectively. End-to-end deep learning approaches using routine H&E-stained slides, trained separately on male and female patients with HGG, may allow for identifying sex-specific histopathological attributes of the TME associated with survival and, ultimately, build patient-centric prognostic risk assessment models.
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- 2024
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4. Macrophage migration inhibitory factor as a therapeutic target in neuro-oncology: A review.
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Jarmula J, Lee J, Lauko A, Rajappa P, Grabowski MM, Dhawan A, Chen P, Bucala R, Vogelbaum MA, and Lathia JD
- Abstract
Primary central nervous system (CNS) tumors affect tens of thousands of patients each year, and there is a significant need for new treatments. Macrophage migration inhibitory factor (MIF) is a cytokine implicated in multiple tumorigenic processes such as cell proliferation, vascularization, and immune evasion and is therefore a promising therapeutic target in primary CNS tumors. There are several MIF-directed treatments available, including small-molecule inhibitors, peptide drugs, and monoclonal antibodies. However, only a small number of these drugs have been tested in preclinical models of primary CNS tumors, and even fewer have been studied in patients. Moreover, the brain has unique therapeutic requirements that further make effective targeting challenging. In this review, we summarize the latest functions of MIF in primary CNS tumor initiation and progression. We also discuss advances in MIF therapeutic development and ongoing preclinical studies and clinical trials. Finally, we discuss potential future MIF therapies and the strategies required for successful clinical translation., Competing Interests: R.B. serves on the clinical advisory board for OncoOne and is an inventor on Yale managed patents for therapeutic MIF antagonists. M.A.V. reports institutional clinical trial contracts with Infuseon, Oncosynergy, and DeNovo; Honoraria from Biodexa, Servier; and being named as a coinventor on pending and issued patents held by the Cleveland Clinic and Moffitt Cancer Center relating to cancer therapies, but these are not directly relevant to this review. J.D.L. reports being named as a coinventor on pending and issued patents held by the Cleveland Clinic relating to cancer therapies, but these are not directly relevant to this review., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)
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- 2024
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5. Journey through tumorverse: Creating models to decode PXA mysteries.
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Bukenya G, Sloan AR, and Lathia JD
- Abstract
Pleomorphic xanthoastrocytoma (PXA) is a rare pediatric low-grade glioma (pLGG), of which 60%-80% exhibit the BRAF V600E mutation, that enhances the aggressiveness and progression to an eventual pediatric high-grade glioma (pHGG). Despite the aggressiveness of this mutational status, the mechanisms underlying the progression of BRAF V600E tumors remain poorly understood, primarily due to limited insights into their in vivo growth dynamics. In this issue, Rajappa and colleagues leverage a novel immunocompetent RCAS-BRAF V600E murine glioma model to profile the immunological dynamics taking place in BRAF V600E pLGG., Competing Interests: The authors have no competing interests., (© 2024 The Author(s).)
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- 2024
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6. γ-aminobutyric acid receptor B signaling drives glioblastoma in females in an immune-dependent manner.
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Pathak A, Palasalava S, Knott MV, Colon B, Ciervo E, Zhou Y, Mitchell J, Pumar OT, Wong HKA, Zhang L, Susic N, Shah KH, Kay K, Chin D, Johnson S, Cheng F, Lyssiotis CA, Watson DC, Ceccarelli M, Shah A, Wahl DR, Lathia JD, and Bayik D
- Abstract
Sex differences in immune responses impact cancer outcomes and treatment response, including in glioblastoma (GBM). However, host factors underlying sex specific immune-cancer interactions are poorly understood. Here, we identify the neurotransmitter γ-aminobutyric acid (GABA) as a driver of GBM-promoting immune response in females. We demonstrated that GABA receptor B (GABBR) signaling enhances L-Arginine metabolism and nitric oxide synthase 2 (NOS2) expression in female granulocytic myeloid-derived suppressor cells (gMDSCs). GABBR agonist and GABA analog promoted GBM growth in females in an immune-dependent manner, while GABBR inhibition reduces gMDSC NOS2 production and extends survival only in females. Furthermore, female GBM patients have enriched GABA transcriptional signatures compared to males, and the use of GABA analogs in GBM patients is associated with worse short-term outcomes only in females. Collectively, these results highlight that GABA modulates anti-tumor immune response in a sex-specific manner, supporting future assessment of GABA pathway inhibitors as part of immunotherapy approaches., Competing Interests: Conflict of interest: In the past three years, C.A.L. has consulted for Astellas Pharmaceuticals, Odyssey Therapeutics, Third Rock Ventures, and T-Knife Therapeutics, and is an inventor on patents pertaining to Kras regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting the GOT1-ME1 pathway as a therapeutic approach (US Patent No: 2015126580-A1, 05/07/2015; US Patent No: 20190136238, 05/09/2019; International Patent No: WO2013177426-A2, 04/23/2015). J.D.L reports being named as a co-inventor on pending and issued patents held by the Cleveland Clinic relating to cancer therapies, but these are not directly relevant to this work.
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- 2024
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7. EGFR amplification and EGFRvIII predict and participate in TAT-Cx43266-283 antitumor response in preclinical glioblastoma models.
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Álvarez-Vázquez A, San-Segundo L, Cerveró-García P, Flores-Hernández R, Ollauri-Ibáñez C, Segura-Collar B, Hubert CG, Morrison G, Pollard SM, Lathia JD, Sánchez-Gómez P, and Tabernero A
- Subjects
- Animals, Humans, Mice, Erlotinib Hydrochloride pharmacology, Tumor Cells, Cultured, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells pathology, Neoplastic Stem Cells metabolism, Glioblastoma drug therapy, Glioblastoma pathology, Glioblastoma metabolism, ErbB Receptors genetics, ErbB Receptors metabolism, Brain Neoplasms drug therapy, Brain Neoplasms pathology, Brain Neoplasms metabolism, Gene Amplification, Temozolomide pharmacology, Xenograft Model Antitumor Assays
- Abstract
Background: Glioblastoma (GBM) commonly displays epidermal growth factor receptor (EGFR) alterations (mainly amplification and EGFRvIII) and TAT-Cx43266-283 is a Src-inhibitory peptide with antitumor properties in preclinical GBM models. Given the link between EGFR and Src, the aim of this study was to explore the role of EGFR in the antitumor effects of TAT-Cx43266-283., Methods: The effect of TAT-Cx43266-283, temozolomide (TMZ), and erlotinib (EGFR inhibitor) was studied in patient-derived GBM stem cells (GSCs) and murine neural stem cells (NSCs) with and without EGFR alterations, in vitro and in vivo. EGFR alterations were analyzed by western blot and fluorescence in situ hybridization in these cells, and compared with Src activity and survival in GBM samples from The Cancer Genome Atlas., Results: The effect of TAT-Cx43266-283 correlated with EGFR alterations in a set of patient-derived GSCs and was stronger than that exerted by TMZ and erlotinib. In fact, TAT-Cx43266-283 only affected NSCs with EGFR alterations, but not healthy NSCs. EGFR alterations correlated with Src activity and poor survival in GBM patients. Finally, tumors generated from NSCs with EGFR alterations showed a decrease in growth, invasiveness, and vascularization after treatment with TAT-Cx43266-283, which enhanced the survival of immunocompetent mice., Conclusions: Clinically relevant EGFR alterations are predictors of TAT-Cx43266-283 response and part of its mechanism of action, even in TMZ- and erlotinib-resistant GSCs. TAT-Cx43266-283 targets NSCs with GBM-driver mutations, including EGFR alterations, in an immunocompetent GBM model in vivo, suggesting a promising effect on GBM recurrence. Together, this study represents an important step toward the clinical application of TAT-Cx43266-283., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)
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- 2024
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8. Cell surface CD55 traffics to the nucleus leading to cisplatin resistance and stemness by inducing PRC2 and H3K27 trimethylation on chromatin in ovarian cancer.
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Bharti R, Dey G, Khan D, Myers A, Huffman OG, Saygin C, Braley C, Richards E, Sangwan N, Willard B, Lathia JD, Fox PL, Lin F, Jha BK, Brown JM, Yu JS, Dwidar M, Joehlin-Price A, Vargas R, Michener CM, Longworth MS, and Reizes O
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- Humans, Female, Animals, Mice, Cell Line, Tumor, Methylation, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Protein Transport, Ovarian Neoplasms drug therapy, Ovarian Neoplasms metabolism, Ovarian Neoplasms pathology, Ovarian Neoplasms genetics, Cisplatin pharmacology, Drug Resistance, Neoplasm genetics, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Neoplastic Stem Cells drug effects, CD55 Antigens metabolism, CD55 Antigens genetics, Histones metabolism, Cell Nucleus metabolism, Chromatin metabolism
- Abstract
Background: Platinum resistance is the primary cause of poor survival in ovarian cancer (OC) patients. Targeted therapies and biomarkers of chemoresistance are critical for the treatment of OC patients. Our previous studies identified cell surface CD55, a member of the complement regulatory proteins, drives chemoresistance and maintenance of cancer stem cells (CSCs). CSCs are implicated in tumor recurrence and metastasis in multiple cancers., Methods: Protein localization assays including immunofluorescence and subcellular fractionation were used to identify CD55 at the cell surface and nucleus of cancer cells. Protein half-life determinations were used to compare cell surface and nuclear CD55 stability. CD55 deletion mutants were generated and introduced into cancer cells to identify the nuclear trafficking code, cisplatin sensitivity, and stem cell frequency that were assayed using in vitro and in vivo models. Detection of CD55 binding proteins was analyzed by immunoprecipitation followed by mass spectrometry. Target pathways activated by CD55 were identified by RNA sequencing., Results: CD55 localizes to the nucleus of a subset of OC specimens, ascites from chemoresistant patients, and enriched in chemoresistant OC cells. We determined that nuclear CD55 is glycosylated and derived from the cell surface pool of CD55. Nuclear localization is driven by a trafficking code containing the serine/threonine (S/T) domain of CD55. Nuclear CD55 is necessary for cisplatin resistance, stemness, and cell proliferation in OC cells. CD55 S/T domain is necessary for nuclear entry and inducing chemoresistance to cisplatin in both in vitro and in vivo models. Deletion of the CD55 S/T domain is sufficient to sensitize chemoresistant OC cells to cisplatin. In the nucleus, CD55 binds and attenuates the epigenetic regulator and tumor suppressor ZMYND8 with a parallel increase in H3K27 trimethylation and members of the Polycomb Repressive Complex 2., Conclusions: For the first time, we show CD55 localizes to the nucleus in OC and promotes CSC and chemoresistance. Our studies identify a therapeutic mechanism for treating platinum resistant ovarian cancer by blocking CD55 nuclear entry., (© 2024. The Author(s).)
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- 2024
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9. Cancer stem cell hypothesis 2.0 in glioblastoma: Where are we now and where are we going?
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Sloan AR, Silver DJ, Kint S, Gallo M, and Lathia JD
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- Humans, Animals, Glioblastoma pathology, Glioblastoma metabolism, Glioblastoma genetics, Neoplastic Stem Cells pathology, Neoplastic Stem Cells metabolism, Brain Neoplasms pathology, Brain Neoplasms metabolism, Brain Neoplasms genetics
- Abstract
Over the past 2 decades, the cancer stem cell (CSC) hypothesis has provided insight into many malignant tumors, including glioblastoma (GBM). Cancer stem cells have been identified in patient-derived tumors and in some mouse models, allowing for a deeper understanding of cellular and molecular mechanisms underlying GBM growth and therapeutic resistance. The CSC hypothesis has been the cornerstone of cellular heterogeneity, providing a conceptual and technical framework to explain this longstanding phenotype in GBM. This hypothesis has evolved to fit recent insights into how cellular plasticity drives tumor growth to suggest that CSCs do not represent a distinct population but rather a cellular state with substantial plasticity that can be achieved by non-CSCs under specific conditions. This has further been reinforced by advances in genomics, including single-cell approaches, that have used the CSC hypothesis to identify multiple putative CSC states with unique properties, including specific developmental and metabolic programs. In this review, we provide a historical perspective on the CSC hypothesis and its recent evolution, with a focus on key functional phenotypes, and provide an update on the definition for its use in future genomic studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
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- 2024
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10. Hallmarks of sex bias in immuno-oncology: mechanisms and therapeutic implications.
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Xiao T, Lee J, Gauntner TD, Velegraki M, Lathia JD, and Li Z
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- Female, Humans, Male, Epigenesis, Genetic, Gonadal Steroid Hormones metabolism, Gonadal Steroid Hormones immunology, Sex Characteristics, Sex Factors, Sexism, Immunotherapy methods, Neoplasms immunology, Neoplasms therapy
- Abstract
Sex differences are present across multiple non-reproductive organ cancers, with male individuals generally experiencing higher incidence of cancer with poorer outcomes. Although some mechanisms underlying these differences are emerging, the immunological basis is not well understood. Observations from clinical trials also suggest a sex bias in conventional immunotherapies with male individuals experiencing a more favourable response and female individuals experiencing more severe adverse events to immune checkpoint blockade. In this Perspective article, we summarize the major biological hallmarks underlying sex bias in immuno-oncology. We focus on signalling from sex hormones and chromosome-encoded gene products, along with sex hormone-independent and chromosome-independent epigenetic mechanisms in tumour and immune cells such as myeloid cells and T cells. Finally, we highlight opportunities for future studies on sex differences that integrate sex hormones and chromosomes and other emerging cancer hallmarks such as ageing and the microbiome to provide a more comprehensive view of how sex differences underlie the response in cancer that can be leveraged for more effective immuno-oncology approaches., (© 2024. Springer Nature Limited.)
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- 2024
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11. MGMT Methylation and Differential Survival Impact by Sex in Glioblastoma.
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Barnett AE, Ozair A, Bamashmos AS, Li H, Bosler DS, Yeaney G, Ali A, Peereboom DM, Lathia JD, and Ahluwalia MS
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Introduction : Sex differences in glioblastoma (GBM) have been observed in incidence, genetic and epigenetic alterations, and immune response. These differences have extended to the methylation of the MGMT promoter, which critically impacts temozolomide resistance. However, the association between sex, MGMT methylation, and survival is poorly understood, which this study sought to evaluate. Methods : A retrospective cohort study was conducted and reported following STROBE guidelines, based on adults with newly diagnosed GBM who received their first surgical intervention at Cleveland Clinic (Ohio, USA) between 2012 and 2018. Kaplan-Meier and multivariable Cox proportional hazards models were used to analyze the association between sex and MGMT promoter methylation status on overall survival (OS). MGMT was defined as methylated if the mean of CpG 1-5 ≥ 12. Propensity score matching was performed on a subset of patients to evaluate the effect of individual CpG site methylation. Results : A total of 464 patients had documented MGMT methylation status with a mean age of 63.4 (range 19-93) years. A total of 170 (36.6%) were female, and 133 (28.7%) received gross total resection as a first intervention. A total of 42.5% were MGMT methylated, with females more often having MGMT methylation than males (52.1% vs. 37.4%, p = 0.004). In univariable analysis, OS was significantly longer for MGMT promoter methylated than un-methylated groups for females (2 yr: 36.8% vs. 11.1%; median: 18.7 vs. 9.5 months; p = 0.001) but not for males (2 yr: 24.3% vs. 12.2%; median: 12.4 vs. 11.3 months; p = 0.22, p for MGMT-sex interaction = 0.02). In multivariable analysis, MGMT un-methylated versus methylated promoter females (2.07; 95% CI, 1.45-2.95; p < 0.0001) and males (1.51; 95% CI, 1.14-2.00; p = 0.004) had worse OS. Within the MGMT promoter methylated group, males had significantly worse OS than females (1.42; 95% CI: 1.01-1.99; p = 0.04). Amongst patients with data on MGMT CpG promoter site methylation values ( n = 304), the median (IQR) of CpG mean methylation was 3.0% (2.0, 30.5). Females had greater mean CpG methylation than males (11.0 vs. 3.0, p < 0.002) and higher per-site CpG methylation with a significant difference at CPG 1, 2, and 4 ( p < 0.008). After propensity score matching, females maintained a significant survival benefit (18.7 vs. 10.0 months, p = 0.004) compared to males (13.0 vs. 13.6 months, p = 0.76), and the pattern of difference was significant (P for CpG-sex interaction = 0.03). Conclusions : In this study, females had higher mean and individual CpG site methylation and received a greater PFS and OS benefit by MGMT methylation that was not seen in males despite equal degrees of CpG methylation.
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- 2024
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12. Androgen loss weakens anti-tumor immunity and accelerates brain tumor growth.
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Lee J, Chung YM, Curtin L, Silver DJ, Hao Y, Li C, Volovetz J, Hong ES, Jarmula J, Wang SZ, Kay KE, Berens M, Nicosia M, Swanson KR, Sharifi N, and Lathia JD
- Abstract
Many cancers, including glioblastoma (GBM), have a male-biased sex difference in incidence and outcome. The underlying reasons for this sex bias are unclear but likely involve differences in tumor cell state and immune response. This effect is further amplified by sex hormones, including androgens, which have been shown to inhibit anti-tumor T cell immunity. Here, we show that androgens drive anti-tumor immunity in brain tumors, in contrast to its effect in other tumor types. Upon castration, tumor growth was accelerated with attenuated T cell function in GBM and brain tumor models, but the opposite was observed when tumors were located outside the brain. Activity of the hypothalamus-pituitary-adrenal gland (HPA) axis was increased in castrated mice, particularly in those with brain tumors. Blockade of glucocorticoid receptors reversed the accelerated tumor growth in castrated mice, indicating that the effect of castration was mediated by elevated glucocorticoid signaling. Furthermore, this mechanism was not GBM specific, but brain specific, as hyperactivation of the HPA axis was observed with intracranial implantation of non-GBM tumors in the brain. Together, our findings establish that brain tumors drive distinct endocrine-mediated mechanisms in the androgen-deprived setting and highlight the importance of organ-specific effects on anti-tumor immunity., Competing Interests: Competing interests N.S. is a co-inventor on a Cleveland Clinic patent on HSD3B1. The other authors declare no competing interest.
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- 2024
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13. miR-644a is a tumor cell-intrinsic mediator of sex bias in glioblastoma.
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Hong ES, Wang SZ, Ponti AK, Hajdari N, Lee J, Mulkearns-Hubert EE, Volovetz J, Kay KE, Lathia JD, and Dhawan A
- Abstract
Background: Biological sex is an important risk factor for glioblastoma (GBM), with males having a higher incidence and poorer prognosis. The mechanisms for this sex bias are thought to be both tumor intrinsic and tumor extrinsic. MicroRNAs (miRNAs), key post-transcriptional regulators of gene expression, have been previously linked to sex differences in various cell types and diseases, but their role in the sex bias of GBM remains unknown., Methods: We leveraged previously published paired miRNA and mRNA sequencing of 39 GBM patients (22 male, 17 female) to identify sex-biased miRNAs. We further interrogated a separate single-cell RNA sequencing dataset of 110 GBM patients to examine whether differences in miRNA target gene expression were tumor cell intrinsic or tumor cell extrinsic. Results were validated in a panel of patient-derived cell models., Results: We identified 10 sex-biased miRNAs ( a
djusted < 0.1), of which 3 were more highly expressed in males and 7 more highly expressed in females. Of these, miR-644a was higher in females, and increased expression of miR-644a target genes was significantly associated with decreased overall survival (HR 1.3, p = 0.02). Furthermore, analysis of an independent single-cell RNA sequencing dataset confirmed sex-specific expression of miR-644a target genes in tumor cells ( p < 10-15 ). Among patient derived models, miR-644a was expressed a median of 4.8-fold higher in females compared to males., Conclusions: Our findings implicate miR-644a as a candidate tumor cell-intrinsic regulator of sex-biased gene expression in GBM., Competing Interests: Conflict of Interest: All authors declare no conflicts of interest.- Published
- 2024
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14. An immunosuppressive vascular niche drives macrophage polarization and immunotherapy resistance in glioblastoma.
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Yang F, Akhtar MN, Zhang D, El-Mayta R, Shin J, Dorsey JF, Zhang L, Xu X, Guo W, Bagley SJ, Fuchs SY, Koumenis C, Lathia JD, Mitchell MJ, Gong Y, and Fan Y
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- Animals, Mice, Endothelial Cells pathology, Cell Line, Tumor, Macrophages, Immunosuppression Therapy, Glioblastoma genetics, Brain Neoplasms genetics
- Abstract
Cancer immunity is subjected to spatiotemporal regulation by leukocyte interaction with neoplastic and stromal cells, contributing to immune evasion and immunotherapy resistance. Here, we identify a distinct mesenchymal-like population of endothelial cells (ECs) that form an immunosuppressive vascular niche in glioblastoma (GBM). We reveal a spatially restricted, Twist1/SATB1-mediated sequential transcriptional activation mechanism, through which tumor ECs produce osteopontin to promote immunosuppressive macrophage (Mφ) phenotypes. Genetic or pharmacological ablation of Twist1 reverses Mφ-mediated immunosuppression and enhances T cell infiltration and activation, leading to reduced GBM growth and extended mouse survival, and sensitizing tumor to chimeric antigen receptor T immunotherapy. Thus, these findings uncover a spatially restricted mechanism controlling tumor immunity and suggest that targeting endothelial Twist1 may offer attractive opportunities for optimizing cancer immunotherapy.
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- 2024
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15. Seek and destroy: Development of novel viral therapy for EGFR-expressing tumors.
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O'Connor C and Lathia JD
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Competing Interests: The authors declare no competing interests.
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- 2024
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16. New T-Cell Therapies for Brain Metastasis, CD133 in the Driver's Seat.
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Sloan AR, Thapliyal M, and Lathia JD
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- Humans, Immunotherapy, T-Lymphocytes, Receptors, Antigen, T-Cell metabolism, Immunotherapy, Adoptive, Brain Neoplasms therapy, Brain Neoplasms metabolism
- Abstract
Chimeric antigen receptor (CAR)-T cell immunotherapy has revolutionized cancer therapy for some advanced cancers, but success is predicated on identifying the correct cell surface target. In a recent article, the authors leveraged the cancer stem cell surface antigen CD133 to develop a CAR-T therapy for brain metastasis. See related article by Kieliszek et al., p. 554., (©2023 American Association for Cancer Research.)
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- 2024
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17. Should I stay or should I go? Transsulfuration influences invasion and growth in glioblastoma.
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Ponti AK, Silver DJ, Hine C, and Lathia JD
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- Humans, Cystathionine gamma-Lyase genetics, Cystathionine gamma-Lyase metabolism, Cystathionine metabolism, Oxidative Stress, Reactive Oxygen Species, Glioblastoma genetics, Glioblastoma pathology
- Abstract
A major challenge in treating patients with glioblastoma is the inability to eliminate highly invasive cells with chemotherapy, radiation, or surgical resection. As cancer cells face the issue of replicating or invading neighboring tissue, they rewire their metabolism in a concerted effort to support necessary cellular processes and account for altered nutrient abundance. In this issue of the JCI, Garcia et al. compared an innovative 3D hydrogel-based invasion device to regional patient biopsies through a comprehensive multiomics-based approach paired with a CRISPR knockout screen. Their findings elucidate a role for cystathionine γ-lyase (CTH), an enzyme in the transsulfuration pathway, as a means of regulating the cellular response to oxidative stress. CTH-mediated conversion of cystathionine to cysteine was necessary for regulating reactive oxygen species to support invasion. Meanwhile, inhibition of CTH suppressed the invasive glioblastoma phenotype. However, inhibiting CTH resulted in a larger overall tumor mass. These findings suggest that targeting the transsulfuration pathway may serve as a means of redirecting glioblastoma to proliferate or invade.
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- 2024
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18. Microglial immunometabolism endophenotypes contribute to sex difference in Alzheimer's disease.
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Hou Y, Caldwell JZK, Lathia JD, Leverenz JB, Pieper AA, Cummings J, and Cheng F
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- Humans, Male, Female, Microglia metabolism, Endophenotypes, Sex Characteristics, Glutamates genetics, Glutamates metabolism, Alzheimer Disease pathology
- Abstract
Introduction: The molecular mechanisms that contribute to sex differences, in particular female predominance, in Alzheimer's disease (AD) prevalence, symptomology, and pathology, are incompletely understood., Methods: To address this problem, we investigated cellular metabolism and immune responses ("immunometabolism endophenotype") across AD individuals as a function of sex with diverse clinical diagnosis of cognitive status at death (cogdx), Braak staging, and Consortium to Establish a Registry for AD (CERAD) scores using human cortex metabolomics and transcriptomics data from the Religious Orders Study / Memory and Aging Project (ROSMAP) cohort., Results: We identified sex-specific metabolites, immune and metabolic genes, and pathways associated with the AD diagnosis and progression. We identified female-specific elevation in glycerophosphorylcholine and N-acetylglutamate, which are AD inflammatory metabolites involved in interleukin (IL)-17 signaling, C-type lectin receptor, interferon signaling, and Toll-like receptor pathways. We pinpointed distinct microglia-specific immunometabolism endophenotypes (i.e., lipid- and amino acid-specific IL-10 and IL-17 signaling pathways) between female and male AD subjects. In addition, female AD subjects showed evidence of diminished excitatory neuron and microglia communications via glutamate-mediated immunometabolism., Discussion: Our results point to new understanding of the molecular basis for female predominance in AD, and warrant future independent validations with ethnically diverse patient cohorts to establish a likely causal relationship of microglial immunometabolism in the sex differences in AD., Highlights: Sex-specific immune metabolites, gene networks and pathways, are associated with Alzheimer's disease pathogenesis and disease progression. Female AD subjects exhibit microglial immunometabolism endophenotypes characterized by decreased glutamate metabolism and elevated interleukin-10 pathway activity. Female AD subjects showed a shift in glutamate-mediated cell-cell communications between excitatory neurons to microglia and astrocyte., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)
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- 2024
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19. Analysis of anemia and iron supplementation among glioblastoma patients reveals sex-biased association between anemia and survival.
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Shenoy G, Slagle-Webb B, Khunsriraksakul C, Pandya Shesh B, Luo J, Khristov V, Smith N, Mansouri A, Zacharia BE, Holder S, Lathia JD, Barnholtz-Sloan JS, and Connor JR
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- Adult, Humans, Male, Female, Iron, Hemoglobins metabolism, Dietary Supplements, Glioblastoma complications, Anemia complications
- Abstract
The association between anemia and outcomes in glioblastoma patients is unclear. We analyzed data from 1346 histologically confirmed adult glioblastoma patients in the TriNetX Research Network. Median hemoglobin and hematocrit levels were quantified for 6 months following diagnosis and used to classify patients as anemic or non-anemic. Associations of anemia and iron supplementation of anemic patients with median overall survival (median-OS) were then studied. Among 1346 glioblastoma patients, 35.9% of male and 40.5% of female patients were classified as anemic using hemoglobin-based WHO guidelines. Among males, anemia was associated with reduced median-OS compared to matched non-anemic males using hemoglobin (HR 1.24; 95% CI 1.00-1.53) or hematocrit-based cutoffs (HR 1.28; 95% CI 1.03-1.59). Among females, anemia was not associated with median-OS using hemoglobin (HR 1.00; 95% CI 0.78-1.27) or hematocrit-based cutoffs (HR: 1.10; 95% CI 0.85-1.41). Iron supplementation of anemic females trended toward increased median-OS (HR 0.61; 95% CI 0.32-1.19) although failing to reach statistical significance whereas no significant association was found in anemic males (HR 0.85; 95% CI 0.41-1.75). Functional transferrin-binding assays confirmed sexually dimorphic binding in resected patient samples indicating underlying differences in iron biology. Anemia among glioblastoma patients exhibits a sex-specific association with survival., (© 2024. The Author(s).)
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- 2024
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20. Targeting NANOG and FAK via Cx26-derived Cell-penetrating Peptides in Triple-negative Breast Cancer.
- Author
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Mulkearns-Hubert EE, Esakov Rhoades E, Ben-Salem S, Bharti R, Hajdari N, Johnson S, Myers A, Smith IN, Bandyopadhyay S, Eng C, Downs E, Lathia JD, and Reizes O
- Subjects
- Humans, Animals, Mice, Cell Line, Tumor, Triple Negative Breast Neoplasms therapy, Nanog Homeobox Protein antagonists & inhibitors, Connexin 26 chemistry, Connexin 26 therapeutic use, Focal Adhesion Kinase 1 antagonists & inhibitors, Cell-Penetrating Peptides chemistry, Cell-Penetrating Peptides therapeutic use
- Abstract
Triple-negative breast cancer (TNBC) represents the most lethal and treatment-resistant breast cancer subtype with limited treatment options. We previously identified a protein complex unique to TNBC composed of the gap junction protein connexin 26 (Cx26), the pluripotency transcription factor NANOG, and focal adhesion kinase (FAK). We sought to determine whether a peptide mimetic of the interaction region of Cx26 attenuated tumor growth in preclinical models. We designed peptides based on Cx26 juxtamembrane domains and performed binding experiments with NANOG and FAK using surface plasmon resonance. Binding studies revealed that the Cx26 C-terminal tail and intracellular loop bound to NANOG and FAK with submicromolar-to-micromolar affinity and that a 5-amino acid sequence in the C-terminal tail of Cx26 (RYCSG) was sufficient for binding. Peptides with high affinity were engineered with a cell-penetrating antennapedia sequence and assessed in functional assays including cell proliferation, tumorsphere formation, and in vivo tumor growth, and downstream signaling changes were measured. The cell-penetrating Cx26 peptide (aCx26-pep) disrupted self-renewal while reducing nuclear FAK and NANOG and inhibiting NANOG target gene expression in TNBC cells but not luminal mammary epithelial cells. In vivo, aCx26-pep reduced tumor growth and proliferation and induced cell death. Here, we provide proof-of-concept that a Cx26 peptide-based strategy inhibits growth and alters NANOG activity specifically in TNBC, indicating the therapeutic potential of this targeting approach., (©2023 American Association for Cancer Research.)
- Published
- 2024
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21. Dose Determination and Administration of Bacterial Extracellular Vesicles for In Vivo Preclinical Studies.
- Author
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Lathia JD and Watson DC
- Subjects
- Animals, Mice, Bacteria metabolism, Extracellular Vesicles metabolism
- Abstract
Essentially all bacteria secrete nano-sized (~20-200 nm) bacterial extracellular vesicles (bEVs) loaded with proteins, lipids, glycans, and nucleic acids. bEVs facilitate interactions among cells of the same species, different microbial species, and even with cells of multicellular organisms in the context of colonization or infection. Their interactions with host organism immune cell receptors vary depending on the producing bacterial species and are now being harnessed for the development of bEVs as a potential immunotherapeutic platform. Both basic/mechanistic and preclinical therapeutic development studies are thus increasing in number and require implementation of methods for multiparametric analytical characterization as well as in vivo administration in preclinical animal models of disease. We summarize a variety of analytical methods that can be used to calculate bEV dose for preparations made from diverse bacterial sources (including sterility testing, total protein concentration, particle concentration, and lipopolysaccharide concentration). We also describe basic methodology for intravenous administration of bEV preparations via tail vein injection in laboratory mice. Throughout the description of methodology, we highlight potential pitfalls and alternatives to further equip the reader for troubleshooting should challenges arise. Robust and reproducible characterization is a prerequisite of bEV preparation quality control and consistent dosing during preclinical development. This will allow for more streamlined testing of candidate therapeutic bEVs within a given research laboratory, and furthermore facilitate reproducibility of findings across laboratories., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2024
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22. 'Slicing' glioblastoma drivers with the Swiss cheese model.
- Author
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Teran Pumar OY, Lathia JD, Watson DC, and Bayik D
- Subjects
- Humans, Epigenesis, Genetic, Glioblastoma pathology
- Abstract
The Swiss cheese model is used to assess risks and explain accidents in a variety of industries. This model can be applied to dissect the homeostatic mechanisms whose cumulative dysregulation contributes to disease states, including cancer. Using glioblastoma (GBM) as an exemplar, we discuss how specific protumorigenic mechanisms collectively drive disease by affecting genomic integrity, epigenetic regulation, metabolic homeostasis, and antitumor immunity. We further highlight how host factors, such as hormonal differences and aging, impact this process, and the interplay between these 'system failures' that enable tumor progression and foster therapeutic resistance. Finally, we examine therapies that consider the interactions between these elements, which may comprise more effective approaches given the multifaceted protumorigenic mechanisms that drive GBM., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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23. Iron inhibits glioblastoma cell migration and polarization.
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Shenoy G, Kheirabadi S, Ataie Z, Sahu AP, Palsa K, Wade Q, Khunsriraksakul C, Khristov V, Slagle-Webb B, Lathia JD, Wang HG, Sheikhi A, and Connor JR
- Subjects
- Humans, Cell Movement genetics, Brain metabolism, Cell Line, Tumor, Cell Proliferation, Glioblastoma metabolism, Brain Neoplasms metabolism
- Abstract
Glioblastoma is one of the deadliest malignancies facing modern oncology today. The ability of glioblastoma cells to diffusely spread into neighboring healthy brain makes complete surgical resection nearly impossible and contributes to the recurrent disease faced by most patients. Although research into the impact of iron on glioblastoma has addressed proliferation, there has been little investigation into how cellular iron impacts the ability of glioblastoma cells to migrate-a key question, especially in the context of the diffuse spread observed in these tumors. Herein, we show that increasing cellular iron content results in decreased migratory capacity of human glioblastoma cells. The decrease in migratory capacity was accompanied by a decrease in cellular polarization in the direction of movement. Expression of CDC42, a Rho GTPase that is essential for both cellular migration and establishment of polarity in the direction of cell movement, was reduced upon iron treatment. We then analyzed a single-cell RNA-seq dataset of human glioblastoma samples and found that cells at the tumor periphery had a gene signature that is consistent with having lower levels of cellular iron. Altogether, our results suggest that cellular iron content is impacting glioblastoma cell migratory capacity and that cells with higher iron levels exhibit reduced motility., (© 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
- Published
- 2023
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24. Recovery of Forearm and Fine Digit Function After Chronic Spinal Cord Injury by Simultaneous Blockade of Inhibitory Matrix Chondroitin Sulfate Proteoglycan Production and the Receptor PTPσ.
- Author
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Milton AJ, Kwok JCF, McClellan J, Randall SG, Lathia JD, Warren PM, Silver DJ, and Silver J
- Subjects
- Animals, Female, Rats, Chondroitin ABC Lyase pharmacology, Nerve Regeneration physiology, Rats, Sprague-Dawley, Receptor-Like Protein Tyrosine Phosphatases, Class 2, Spinal Cord, Forelimb, Chondroitin Sulfate Proteoglycans pharmacology, Spinal Cord Injuries
- Abstract
Spinal cord injuries (SCI), for which there are limited effective treatments, result in enduring paralysis and hypoesthesia, in part because of the inhibitory microenvironment that develops and limits regeneration/sprouting, especially during chronic stages. Recently, we discovered that targeted enzymatic removal of the inhibitory chondroitin sulfate proteoglycan (CSPG) component of the extracellular and perineuronal net (PNN) matrix via Chondroitinase ABC (ChABC) rapidly restored robust respiratory function to the previously paralyzed hemi-diaphragm after remarkably long times post-injury (up to 1.5 years) following a cervical level 2 lateral hemi-transection. Importantly, ChABC treatment at cervical level 4 in this chronic model also elicited improvements in gross upper arm function. In the present study, we focused on arm and hand function, seeking to highlight and optimize crude as well as fine motor control of the forearm and digits at lengthy chronic stages post-injury. However, instead of using ChABC, we utilized a novel and more clinically relevant systemic combinatorial treatment strategy designed to simultaneously reduce and overcome inhibitory CSPGs. Following a 3-month upper cervical spinal hemi-lesion using adult female Sprague Dawley rats, we show that the combined treatment had a profound effect on functional recovery of the chronically paralyzed forelimb and paw, as well as on precision movements of the digits. The regenerative and immune system related events that we describe deepen our basic understanding of the crucial role of CSPG-mediated inhibition via the PTPσ receptor in constraining functional synaptic plasticity at lengthy time points following SCI, hopefully leading to clinically relevant translational benefits.
- Published
- 2023
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25. Homeostatic iron regulatory protein drives glioblastoma growth via tumor cell-intrinsic and sex-specific responses.
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Troike KM, Wang SZ, Silver DJ, Lee J, Mulkearns-Hubert EE, Hajdari N, Ghosh PK, Kay KE, Beilis JL, Mitchell SE, Bishop CW, Hong ES, Artomov M, Hubert CG, Rajappa P, Connor JR, Fox PL, Kristensen BW, and Lathia JD
- Abstract
Background: Glioblastoma (GBM) displays alterations in iron that drive proliferation and tumor growth. Iron regulation is complex and involves many regulatory mechanisms, including the homeostatic iron regulator ( HFE ) gene, which encodes the homeostatic iron regulatory protein. While HFE is upregulated in GBM and correlates with poor survival outcomes, the function of HFE in GBM remains unclear., Methods: We interrogated the impact of cell-intrinsic Hfe expression on proliferation and survival of intracranially implanted animals through genetic gain- and loss-of-function approaches in syngeneic mouse glioma models, along with in vivo immune assessments. We also determined the expression of iron-associated genes and their relationship to survival in GBM using public data sets and used transcriptional profiling to identify differentially expressed pathways in control compared to Hfe -knockdown cells., Results: Overexpression of Hfe accelerated GBM proliferation and reduced animal survival, whereas suppression of Hfe induced apoptotic cell death and extended survival, which was more pronounced in females and associated with attenuation of natural killer cells and CD8+ T cell activity. Analysis of iron gene signatures in Hfe -knockdown cells revealed alterations in the expression of several iron-associated genes, suggesting global disruption of intracellular iron homeostasis. Further analysis of differentially expressed pathways revealed oxidative stress as the top pathway upregulated following Hfe loss. Hfe knockdown indeed resulted in enhanced
55 Fe uptake and generation of reactive oxygen species., Conclusions: These findings reveal an essential function for HFE in GBM cell growth and survival, as well as a sex-specific interaction with the immune response., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)- Published
- 2023
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26. The missing link? LGMN connects hypoxia and immunosuppression in glioblastoma.
- Author
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Mitchell J, Colon B, Bayik D, and Lathia JD
- Subjects
- Humans, Cysteine Endopeptidases physiology, Immunosuppression Therapy adverse effects, Hypoxia, Glioblastoma
- Abstract
In this issue, Pang and colleagues
1 identify the protease legumain as a potential immunotherapy target in glioblastoma that drives tumor-associated macrophages in response to hypoxia., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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27. Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.
- Author
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Kay KE, Lee J, Hong ES, Beilis J, Dayal S, Wesley E, Mitchell S, Wang SZ, Silver DJ, Volovetz J, Johnson S, McGraw M, Grabowski MM, Lu T, Freytag L, Narayana V, Freytag S, Best SA, Whittle JR, Wang Z, Reizes O, Yu JS, Hazen SL, Brown JM, Bayik D, and Lathia JD
- Abstract
The glioblastoma microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly impact the immune system, but the mechanisms driving these interactions are not completely clear. Here we demonstrate that the polyamine metabolite spermidine is elevated in the glioblastoma tumor microenvironment. Exogenous administration of spermidine drives tumor aggressiveness in an immune-dependent manner in pre-clinical mouse models via reduction of CD8+ T cell frequency and phenotype. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in spermidine synthesis, did not impact cancer cell growth in vitro but did result in extended survival. Furthermore, glioblastoma patients with a more favorable outcome had a significant reduction in spermidine compared to patients with a poor prognosis. Our results demonstrate that spermidine functions as a cancer cell-derived metabolite that drives tumor progression by reducing CD8+T cell number and function.
- Published
- 2023
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28. The one-two punch: TIM-3 blockade targets immune and tumor cells to knock out pediatric brain tumors.
- Author
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Lee J and Lathia JD
- Subjects
- Child, Humans, Hepatitis A Virus Cellular Receptor 2 genetics, Glioma drug therapy, Glioma genetics, Brain Neoplasms drug therapy, Brain Neoplasms genetics
- Abstract
Diffuse midline gliomas (DMGs) pose treatment challenges due to their location within the brainstem and invasive nature. Although classical immune checkpoint inhibitors have demonstrated limited success in clinical trials, Ausejo-Mauleon et al. demonstrate TIM-3 is an effective DMG strategy, targeting both immune and tumor cells for dual therapeutic benefit., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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29. Metaorganismal choline metabolism shapes olfactory perception.
- Author
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Massey WJ, Kay KE, Jaramillo TC, Horak AJ 3rd, Cao S, Osborn LJ, Banerjee R, Mrdjen M, Hamoudi MK, Silver DJ, Burrows AC, Brown AL, Reizes O, Lathia JD, Wang Z, Hazen SL, and Brown JM
- Subjects
- Animals, Mice, Bacteria metabolism, Choline metabolism, Methylamines metabolism, Female, Mice, Inbred C57BL, Olfactory Perception
- Abstract
Microbes living in the intestine can regulate key signaling processes in the central nervous system that directly impact brain health. This gut-brain signaling axis is partially mediated by microbe-host-dependent immune regulation, gut-innervating neuronal communication, and endocrine-like small molecule metabolites that originate from bacteria to ultimately cross the blood-brain barrier. Given the mounting evidence of gut-brain crosstalk, a new therapeutic approach of "psychobiotics" has emerged, whereby strategies designed to primarily modify the gut microbiome have been shown to improve mental health or slow neurodegenerative diseases. Diet is one of the most powerful determinants of gut microbiome community structure, and dietary habits are associated with brain health and disease. Recently, the metaorganismal (i.e., diet-microbe-host) trimethylamine N-oxide (TMAO) pathway has been linked to the development of several brain diseases including Alzheimer's, Parkinson's, and ischemic stroke. However, it is poorly understood how metaorganismal TMAO production influences brain function under normal physiological conditions. To address this, here we have reduced TMAO levels by inhibiting gut microbe-driven choline conversion to trimethylamine (TMA), and then performed comprehensive behavioral phenotyping in mice. Unexpectedly, we find that TMAO is particularly enriched in the murine olfactory bulb, and when TMAO production is blunted at the level of bacterial choline TMA lyase (CutC/D), olfactory perception is altered. Taken together, our studies demonstrate a previously underappreciated role for the TMAO pathway in olfactory-related behaviors., Competing Interests: Conflict of interest W. J. M., K. E. K., T. C. J., A. H., S. C., L. J. O., R. B., D. J. S., A. B., A. L. B., O. R., J. D. L., and J. M. B. all declare no competing financial interests. Z. W. and S. L. H. report being named as co-inventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics. S. L. H. also reports being a paid consultant for Zehna Therapeutics. S. L. H reports having received research funds from Procter & Gamble, Zehna Therapeutics and Roche Diagnostics. Z. W. and S. L. H. report being eligible to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland Heart Lab, and Procter & Gamble, and S. L. H. from Zehna Therapeutics., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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30. Let the Guard Down: cAMP Activators Can Improve Immunotherapy in GBM.
- Author
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Lee J, Kay KE, Vogelbaum MA, and Lathia JD
- Subjects
- Humans, T-Lymphocytes pathology, Immunotherapy, Neoplastic Stem Cells pathology, Glioblastoma therapy, Glioblastoma pathology, Brain Neoplasms therapy, Brain Neoplasms pathology
- Abstract
Enhancing T-cell infiltration into glioblastoma (GBM) tumors has proven challenging yet remains crucial for improving the efficacy of immunotherapy for patients with this deadly cancer. In this issue, Qin, Huang, Li, and colleagues find that inhibiting vasculature formation driven by cancer stem cells is a promising target to enhance immunotherapy in GBM. See related article by Qin, Huang, Li, et al., p. 1351 (2)., (©2023 American Association for Cancer Research.)
- Published
- 2023
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31. A TOX-ic axis of epigenetic stem cell maintenance and chemoresistance in colon cancer.
- Author
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Hubert CG, Stauffer SR, and Lathia JD
- Subjects
- Humans, Epigenesis, Genetic, Neoplastic Stem Cells, Phenotype, ATP Binding Cassette Transporter, Subfamily G, Member 2, Neoplasm Proteins, Intracellular Signaling Peptides and Proteins, Drug Resistance, Neoplasm genetics, Colonic Neoplasms drug therapy, Colonic Neoplasms genetics
- Abstract
Cancer stem cells drive tumor growth and survival via self-renewal and therapeutic resistance, but the upstream mechanisms are not well defined. In this issue of PLOS Biology, a study in colon cancer reveals a new signalling network that links epigenetic regulation to these phenotypes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Hubert et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2023
- Full Text
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32. Sex-Biased T-cell Exhaustion Drives Differential Immune Responses in Glioblastoma.
- Author
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Lee J, Nicosia M, Hong ES, Silver DJ, Li C, Bayik D, Watson DC, Lauko A, Kay KE, Wang SZ, Johnson S, McGraw M, Grabowski MM, Kish DD, Desai AB, Goodman WA, Cameron SJ, Okada H, Valujskikh A, Fairchild RL, Ahluwalia MS, and Lathia JD
- Subjects
- Male, Female, Mice, Animals, T-Cell Exhaustion, CD8-Positive T-Lymphocytes, Immunotherapy, Immunity, Tumor Microenvironment, Glioblastoma genetics, Brain Neoplasms pathology
- Abstract
Sex differences in glioblastoma (GBM) incidence and outcome are well recognized, and emerging evidence suggests that these extend to genetic/epigenetic and cellular differences, including immune responses. However, the mechanisms driving immunologic sex differences are not fully understood. Here, we demonstrate that T cells play a critical role in driving GBM sex differences. Male mice exhibited accelerated tumor growth, with decreased frequency and increased exhaustion of CD8+ T cells in the tumor. Furthermore, a higher frequency of progenitor exhausted T cells was found in males, with improved responsiveness to anti-PD-1 treatment. Moreover, increased T-cell exhaustion was observed in male GBM patients. Bone marrow chimera and adoptive transfer models indicated that T cell-mediated tumor control was predominantly regulated in a cell-intrinsic manner, partially mediated by the X chromosome inactivation escape gene Kdm6a. These findings demonstrate that sex-biased predetermined behavior of T cells is critical for inducing sex differences in GBM progression and immunotherapy response., Significance: Immunotherapies in patients with GBM have been unsuccessful due to a variety of factors, including the highly immunosuppressive tumor microenvironment in GBM. This study demonstrates that sex-biased T-cell behaviors are predominantly intrinsically regulated, further suggesting sex-specific approaches can be leveraged to potentially improve the therapeutic efficacy of immunotherapy in GBM. See related commentary by Alspach, p. 1966. This article is featured in Selected Articles from This Issue, p. 1949., (©2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2023
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33. The MIF promoter SNP rs755622 is associated with immune activation in glioblastoma.
- Author
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Alban TJ, Grabowski MM, Otvos B, Bayik D, Wang W, Zalavadia A, Makarov V, Troike K, McGraw M, Rabljenovic A, Lauko A, Neumann C, Roversi G, Waite KA, Cioffi G, Patil N, Tran TT, McCortney K, Steffens A, Diaz CM, Brown JM, Egan KM, Horbinski CM, Barnholtz-Sloan JS, Rajappa P, Vogelbaum MA, Bucala R, Chan TA, Ahluwalia MS, and Lathia JD
- Subjects
- Humans, Lactoferrin genetics, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Tumor Microenvironment genetics, Intramolecular Oxidoreductases genetics, Macrophage Migration-Inhibitory Factors genetics, Glioblastoma genetics
- Abstract
Intratumoral heterogeneity is a defining hallmark of glioblastoma, driving drug resistance and ultimately recurrence. Many somatic drivers of microenvironmental change have been shown to affect this heterogeneity and, ultimately, the treatment response. However, little is known about how germline mutations affect the tumoral microenvironment. Here, we find that the single-nucleotide polymorphism (SNP) rs755622 in the promoter of the cytokine macrophage migration inhibitory factor (MIF) is associated with increased leukocyte infiltration in glioblastoma. Furthermore, we identified an association between rs755622 and lactotransferrin expression, which could also be used as a biomarker for immune-infiltrated tumors. These findings demonstrate that a germline SNP in the promoter region of MIF may affect the immune microenvironment and further reveal a link between lactotransferrin and immune activation.
- Published
- 2023
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34. Unrestricted Ketogenic Diet Feeding Enhances Epithelial Ovarian Cancer Growth In Vivo.
- Author
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AlHilli MM, Rhoades EE, Chau D, Tewari S, Reich A, Myers A, Lindner DJ, Lathia JD, Zhang R, Willard B, Cresci G, Berger NA, and Reizes O
- Subjects
- Humans, Female, Mice, Animals, Carcinoma, Ovarian Epithelial, Diet, High-Fat adverse effects, Carbohydrates, Mice, Inbred C57BL, Diet, Ketogenic, Ovarian Neoplasms
- Abstract
The ketogenic diet (KD) is hypothesized to impact tumor progression by altering tumor metabolism. In this study, we assessed the impact of an unrestricted KD on epithelial ovarian cancer (EOC) tumor growth, gene expression, and metabolite concentration in a mouse model. ID8 EOC cells, which were syngeneic with C57Bl/6J mouse strain and transfected with luciferase (ID8-luc), were injectedand monitored for tumor development. Female mice were fed either a strict KD, a high fat/low carbohydrate (HF/LC) diet, or a low fat/high carbohydrate (LF/HC) diet (n = 10 mice per group) ad libitum. EOC tumor growth was monitored weekly, and tumor burden was determined based on luciferase fluorescence (photons/second). At the endpoint (42 days), tumors were collected and processed for RNA sequencing. Plasma and tumor metabolites were evaluated using LC-MS. The KD-fed mice exhibited a statistically significant increase in tumor progression in comparison to the HF/LC- and LF/HC-fed groups (9.1 vs. 2.0 vs. 3.1-fold, respectively, p < 0.001). The EOC tumors of the KD-fed mice exhibited significant enrichment of the peroxisome proliferator-activated receptor (PPAR) signaling and fatty acid metabolism pathways based on the RNA sequencing analysis when compared to the LF/HC- and HF/LC-fed mice. Thus, unrestricted KD diet enhanced tumor progression in our mouse EOC model. KD was associated with the upregulation of fatty acid metabolism and regulation pathways, as well as enrichment of fatty acid and glutamine metabolites.
- Published
- 2023
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35. Water channel aquaporin 4 is required for T cell receptor mediated lymphocyte activation.
- Author
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Nicosia M, Lee J, Beavers A, Kish D, Farr GW, McGuirk PR, Pelletier MF, Lathia JD, Fairchild RL, and Valujskikh A
- Subjects
- Mice, Humans, Animals, Receptors, Antigen, T-Cell, T-Lymphocytes, Signal Transduction, Aquaporin 4 genetics, Aquaporin 4 metabolism, Lymphocyte Activation
- Abstract
Aquaporins are a family of ubiquitously expressed transmembrane water channels implicated in a broad range of physiological functions. We have previously reported that aquaporin 4 (AQP4) is expressed on T cells and that treatment with a small molecule AQP4 inhibitor significantly delays T cell mediated heart allograft rejection. Using either genetic deletion or small molecule inhibitor, we show that AQP4 supports T cell receptor mediated activation of both mouse and human T cells. Intact AQP4 is required for optimal T cell receptor (TCR)-related signaling events, including nuclear translocation of transcription factors and phosphorylation of proximal TCR signaling molecules. AQP4 deficiency or inhibition impairs actin cytoskeleton rearrangements following TCR crosslinking, causing inferior TCR polarization and a loss of TCR signaling. Our findings reveal a novel function of AQP4 in T lymphocytes and identify AQP4 as a potential therapeutic target for preventing TCR-mediated T cell activation., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2023
- Full Text
- View/download PDF
36. Antibody-cytokine fusion breathes new life into glioblastoma therapy.
- Author
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Lee J, Nicosia M, and Lathia JD
- Subjects
- Animals, Mice, Antibodies, Cytokines, Glioblastoma drug therapy
- Abstract
An antibody-cytokine fusion molecule combined with chemotherapy induces tumor regression in mice and patients with recurrent glioblastoma by boosting antitumor immunity (Look et al. ).
- Published
- 2023
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37. Correction: Distinct Cell Adhesion Signature Defines Glioblastoma Myeloid-Derived Suppressor Cell Subsets.
- Author
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Bayik D, Bartels CF, Lovrenert K, Watson DC, Zhang D, Kay K, Lee J, Lauko A, Johnson S, Lo A, Silver DJ, McGraw M, Grabowski M, Mohammadi AM, Veglia F, Fan Y, Vogelbaum MA, Scacheri P, and Lathia JD
- Published
- 2023
- Full Text
- View/download PDF
38. DUB-ling down on the epigenetic regulation of cancer stem cells in glioblastoma.
- Author
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Mulkearns-Hubert EE and Lathia JD
- Subjects
- Humans, Epigenesis, Genetic, Cell Transformation, Neoplastic, Carcinogenesis genetics, Neoplastic Stem Cells, Ubiquitin Thiolesterase, AlkB Homolog 5, RNA Demethylase, Glioblastoma genetics
- Published
- 2023
- Full Text
- View/download PDF
39. Correction: Connexin 43 expression is associated with increased malignancy in prostate cancer cell lines and functions to promote migration.
- Author
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Zhang A, Hitomi M, Bar-Shain N, Dalimov Z, Ellis L, Velpula KK, Fraizer GC, Gourdie RG, and Lathia JD
- Published
- 2023
- Full Text
- View/download PDF
40. Dopamine receptor D2 regulates glioblastoma survival and death through MET and death receptor 4/5.
- Author
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Jeon HM, Oh YT, Shin YJ, Chang N, Kim D, Woo D, Yeup Y, Joo KM, Jo H, Yang H, Lee JK, Kang W, Sa J, Lee WJ, Hale J, Lathia JD, Purow B, Park MJ, Park JB, Nam DH, and Lee J
- Subjects
- Humans, Cell Line, Tumor, Dopamine, Receptors, TNF-Related Apoptosis-Inducing Ligand, Signal Transduction, Receptors, Dopamine D2 metabolism, Glioblastoma pathology
- Abstract
Recent studies indicate that signaling molecules traditionally associated with central nervous system function play critical roles in cancer. Dopamine receptor signaling is implicated in various cancers including glioblastoma (GBM) and it is a recognized therapeutic target, as evidenced by recent clinical trials with a selective dopamine receptor D2 (DRD2) inhibitor ONC201. Understanding the molecular mechanism(s) of the dopamine receptor signaling will be critical for development of potent therapeutic options. Using the human GBM patient-derived tumors treated with dopamine receptor agonists and antagonists, we identified the proteins that interact with DRD2. DRD2 signaling promotes glioblastoma (GBM) stem-like cells and GBM growth by activating MET. In contrast, pharmacological inhibition of DRD2 induces DRD2-TRAIL receptor interaction and subsequent cell death. Thus, our findings demonstrate a molecular circuitry of oncogenic DRD2 signaling in which MET and TRAIL receptors, critical factors for tumor cell survival and cell death, respectively, govern GBM survival and death. Finally, tumor-derived dopamine and expression of dopamine biosynthesis enzymes in a subset of GBM may guide patient stratification for DRD2 targeting therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)
- Published
- 2023
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41. GAP43-dependent mitochondria transfer from astrocytes enhances glioblastoma tumorigenicity.
- Author
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Watson DC, Bayik D, Storevik S, Moreino SS, Sprowls SA, Han J, Augustsson MT, Lauko A, Sravya P, Røsland GV, Troike K, Tronstad KJ, Wang S, Sarnow K, Kay K, Lunavat TR, Silver DJ, Dayal S, Joseph JV, Mulkearns-Hubert E, Ystaas LAR, Deshpande G, Guyon J, Zhou Y, Magaut CR, Seder J, Neises L, Williford SE, Meiser J, Scott AJ, Sajjakulnukit P, Mears JA, Bjerkvig R, Chakraborty A, Daubon T, Cheng F, Lyssiotis CA, Wahl DR, Hjelmeland AB, Hossain JA, Miletic H, and Lathia JD
- Subjects
- Humans, Astrocytes metabolism, Astrocytes pathology, GAP-43 Protein metabolism, GAP-43 Protein therapeutic use, Axons metabolism, Axons pathology, Cell Line, Tumor, Nerve Regeneration, Mitochondria metabolism, Mitochondria pathology, Glioblastoma
- Abstract
The transfer of intact mitochondria between heterogeneous cell types has been confirmed in various settings, including cancer. However, the functional implications of mitochondria transfer on tumor biology are poorly understood. Here we show that mitochondria transfer is a prevalent phenomenon in glioblastoma (GBM), the most frequent and malignant primary brain tumor. We identified horizontal mitochondria transfer from astrocytes as a mechanism that enhances tumorigenesis in GBM. This transfer is dependent on network-forming intercellular connections between GBM cells and astrocytes, which are facilitated by growth-associated protein 43 (GAP43), a protein involved in neuron axon regeneration and astrocyte reactivity. The acquisition of astrocyte mitochondria drives an increase in mitochondrial respiration and upregulation of metabolic pathways linked to proliferation and tumorigenicity. Functionally, uptake of astrocyte mitochondria promotes cell cycle progression to proliferative G2/M phases and enhances self-renewal and tumorigenicity of GBM. Collectively, our findings reveal a host-tumor interaction that drives proliferation and self-renewal of cancer cells, providing opportunities for therapeutic development., (© 2023. The Author(s).)
- Published
- 2023
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42. Lead Optimization of Androgen Receptor-HSP27 Disrupting Agents in Glioblastoma.
- Author
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Li Y, Orahoske C, Salem F, Johnson A, Tannous C, Devole L, Zhang W, Lathia JD, Wang B, and Su B
- Subjects
- Humans, Male, Female, Receptors, Androgen metabolism, HSP27 Heat-Shock Proteins, Cell Line, Tumor, Heat-Shock Proteins, Glioblastoma metabolism
- Abstract
Glioblastoma (GBM) is the most common malignant brain tumor with poor prognosis under the current standard treatment. It is critical to develop new approaches to selectively battle the disease. GBM sex differences suggest that an androgen receptor (AR) is a potential therapeutic target to treat AR-overexpressed GBM. Heat shock 27 kDa protein (HSP27) is a well-documented chaperone protein that stabilizes AR. Inhibition of HSP27 leads to AR degradation, indicating that HSP27 inhibitors could suppress AR activity in GBM. We have identified a lead HSP27 inhibitor that could induce AR degradation. Lead optimization resulted with two new derivatives (compounds 4 and 26 ) showing potent anti-GBM activity and improved drug distribution in comparison to the lead compound. Compounds 4 and 6 exhibit IC
50 s of 35 and 23 nM, respectively, to inhibit cell proliferation and also show significant activity to decrease the tumor growth in vivo .- Published
- 2023
- Full Text
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43. Spatial immunosampling of MRI-defined glioblastoma regions reveals immunologic fingerprint of non-contrast enhancing, infiltrative tumor margins.
- Author
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Grabowski MM, Watson DC, Chung K, Lee J, Bayik D, Lauko A, Alban T, Melenhorst JJ, Chan T, Lathia JD, Ahluwalia MS, and Mohammadi AM
- Abstract
Glioblastoma (GBM) treatment includes maximal safe resection of the core and MRI contrast-enhancing (CE) tumor. Complete resection of the infiltrative non-contrast-enhancing (NCE) tumor rim is rarely achieved. We established a safe, semi-automated workflow for spatially-registered sampling of MRI-defined GBM regions in 19 patients with downstream analysis and biobanking, enabling studies of NCE, wherefrom recurrence/progression typically occurs. Immunophenotyping revealed underrepresentation of myeloid cell subsets and CD8+ T cells in the NCE. While NCE T cells phenotypically and functionally resembled those in matching CE tumor, subsets of activated (CD69
hi ) effector memory CD8+ T cells were overrepresented. Contrarily, CD25hi Tregs and other subsets were underrepresented. Overall, our study demonstrated that MRI-guided, spatially-registered, intraoperative immunosampling is feasible as part of routine GBM surgery. Further elucidation of the shared and spatially distinct microenvironmental biology of GBM will enable development of therapeutic approaches targeting the NCE infiltrative tumor to decrease GBM recurrence., Competing Interests: NICO Corporation provided the NICO Myriad and Tissue Preservation System devices at no cost. MSA declares the following: Research funding from Seagen; Consultation for Bayer, Novocure, Kiyatec, Insightec, GSK, Xoft, Nuvation, Cellularity, SDP Oncology, Apollomics, Prelude, Janssen, Tocagen, Voyager Therapeutics, Viewray, Caris Lifesciences, Pyramid Biosciences, Anheart Therapeutics, Varian Medical Systems, Theraguix; Scientific Advisory Board for Cairn Therapeutics, Pyramid Biosciences, Modifi Biosciences; Stock shareholder of Mimivax, Cytodyn, MedInnovate Advisors LLC. The authors have declared that no other potential conflict of interest exists.- Published
- 2023
- Full Text
- View/download PDF
44. Transferred mitochondria accumulate reactive oxygen species, promoting proliferation.
- Author
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Kidwell CU, Casalini JR, Pradeep S, Scherer SD, Greiner D, Bayik D, Watson DC, Olson GS, Lathia JD, Johnson JS, Rutter J, Welm AL, Zangle TA, and Roh-Johnson M
- Subjects
- Humans, Reactive Oxygen Species metabolism, Signal Transduction, Cell Proliferation, Mitochondria metabolism, Neoplasms pathology
- Abstract
Recent studies reveal that lateral mitochondrial transfer, the movement of mitochondria from one cell to another, can affect cellular and tissue homeostasis. Most of what we know about mitochondrial transfer stems from bulk cell studies and have led to the paradigm that functional transferred mitochondria restore bioenergetics and revitalize cellular functions to recipient cells with damaged or non-functional mitochondrial networks. However, we show that mitochondrial transfer also occurs between cells with functioning endogenous mitochondrial networks, but the mechanisms underlying how transferred mitochondria can promote such sustained behavioral reprogramming remain unclear. We report that unexpectedly, transferred macrophage mitochondria are dysfunctional and accumulate reactive oxygen species in recipient cancer cells. We further discovered that reactive oxygen species accumulation activates ERK signaling, promoting cancer cell proliferation. Pro-tumorigenic macrophages exhibit fragmented mitochondrial networks, leading to higher rates of mitochondrial transfer to cancer cells. Finally, we observe that macrophage mitochondrial transfer promotes tumor cell proliferation in vivo. Collectively these results indicate that transferred macrophage mitochondria activate downstream signaling pathways in a ROS-dependent manner in cancer cells, and provide a model of how sustained behavioral reprogramming can be mediated by a relatively small amount of transferred mitochondria in vitro and in vivo., Competing Interests: CK, JC, SP, SS, DG, DB, DW, GO, JL, JJ, JR, AW, TZ, MR No competing interests declared, (© 2023, Kidwell, Casalini et al.)
- Published
- 2023
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45. WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma.
- Author
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Mitchell K, Sprowls SA, Arora S, Shakya S, Silver DJ, Goins CM, Wallace L, Roversi G, Schafer RE, Kay K, Miller TE, Lauko A, Bassett J, Kashyap A, D'Amato Kass J, Mulkearns-Hubert EE, Johnson S, Alvarado J, Rich JN, Holland EC, Paddison PJ, Patel AP, Stauffer SR, Hubert CG, and Lathia JD
- Subjects
- Humans, Histone-Lysine N-Methyltransferase metabolism, Transcription Factors, Neoplastic Stem Cells pathology, Intracellular Signaling Peptides and Proteins genetics, Glioblastoma drug therapy, Glioblastoma genetics
- Abstract
Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors driven by populations of cancer stem cells (CSCs). However, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy-resistant niche and identified WDR5 as indispensable for this population. WDR5 is a component of the WRAD complex, which promotes SET1 family-mediated Lys4 methylation of histone H3 (H3K4me), associated with positive regulation of transcription. In GBM CSCs, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, including the POU5F1(OCT4)::SOX2 motif. Use of a SOX2/OCT4 reporter demonstrated that WDR5 inhibitor treatment diminished cells with high reporter activity. Furthermore, WDR5 inhibitor treatment and WDR5 knockdown altered the stem cell state, disrupting CSC in vitro growth and self-renewal, as well as in vivo tumor growth. These findings highlight the role of WDR5 and the WRAD complex in maintaining the CSC state and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers., (© 2023 Mitchell et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2023
- Full Text
- View/download PDF
46. EGFR Pathway Expression Persists in Recurrent Glioblastoma Independent of Amplification Status.
- Author
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Dhawan A, Manem VSK, Yeaney G, Lathia JD, and Ahluwalia MS
- Abstract
Background: Glioblastoma mortality is driven by tumour progression or recurrence despite administering a therapeutic arsenal consisting of surgical resection, radiation, and alkylating chemotherapy. The genetic changes underlying tumour progression and chemotherapy resistance are poorly understood., Methods: In this study, we sought to define the relationship between EGFR amplification status, EGFR mRNA expression, and EGFR pathway activity. We compared RNA-sequencing data from matched primary and recurrent tumour samples ( n = 40 patients, 20 with EGFR amplification)., Results: In the setting of glioblastoma recurrence, the EGFR pathway was overexpressed regardless of EGFR-amplification status, suggesting a common genomic endpoint in recurrent glioblastoma, although EGFR amplification did associate with higher EGFR mRNA expression. Three of forty patients in the study cohort had EGFR-amplified tumours and received targeted EGFR therapy. Their molecular subtypes and clinical outcomes did not significantly differ from patients who received conventional chemotherapy., Conclusion: Our findings suggest that while the EGFR amplification may confer a unique molecular profile in primary glioblastoma, pathway analysis reveals upregulation of the EGFR pathway in recurrence, regardless of amplification status. As such, the EGFR pathway may be a key mediator of glioblastoma progression.
- Published
- 2023
- Full Text
- View/download PDF
47. Breaking down the barrier to medulloblastoma treatment: Piezo2 knockout disrupts the BTB and increases vascular permeability.
- Author
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Sprowls SA and Lathia JD
- Subjects
- Mice, Animals, Capillary Permeability, Blood-Brain Barrier pathology, Permeability, Ion Channels genetics, Medulloblastoma genetics, Medulloblastoma pathology, Brain Neoplasms pathology, Cerebellar Neoplasms genetics, Cerebellar Neoplasms pathology
- Abstract
In this issue, Chen et al.
1 show that genetic knockout of Piezo2 in SOX2+ medulloblastoma cells decreased local tissue stiffness, increased drug delivery across the blood-tumor barrier, and improved survival, uncovering a mechanosensitivity-dependent mechanism of action in a mouse model of pediatric brain tumors., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)- Published
- 2023
- Full Text
- View/download PDF
48. Disruption of the Gut Microbiota Confers Cisplatin Resistance in Epithelial Ovarian Cancer.
- Author
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Chambers LM, Esakov Rhoades EL, Bharti R, Braley C, Tewari S, Trestan L, Alali Z, Bayik D, Lathia JD, Sangwan N, Bazeley P, Joehlin-Price AS, Wang Z, Dutta S, Dwidar M, Hajjar A, Ahern PP, Claesen J, Rose P, Vargas R, Brown JM, Michener CM, and Reizes O
- Subjects
- Humans, Female, Mice, Animals, Carcinoma, Ovarian Epithelial drug therapy, Carcinoma, Ovarian Epithelial pathology, Cisplatin therapeutic use, Retrospective Studies, Neoplasm Recurrence, Local drug therapy, Anti-Bacterial Agents pharmacology, Gastrointestinal Microbiome, Ovarian Neoplasms pathology
- Abstract
Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death. Despite initial responses to intervention, up to 80% of patient tumors recur and require additional treatment. Retrospective clinical analysis of patients with ovarian cancer indicates antibiotic use during chemotherapy treatment is associated with poor overall survival. Here, we assessed whether antibiotic (ABX) treatment would impact growth of EOC and sensitivity to cisplatin. Immunocompetent or immunocompromised mice were given untreated control or ABX-containing (metronidazole, ampicillin, vancomycin, and neomycin) water prior to intraperitoneal injection with EOC cells, and cisplatin therapy was administered biweekly until endpoint. Tumor-bearing ABX-treated mice exhibited accelerated tumor growth and resistance to cisplatin therapy compared with control treatment. ABX treatment led to reduced apoptosis, increased DNA damage repair, and enhanced angiogenesis in cisplatin-treated tumors, and tumors from ABX-treated mice contained a higher frequency of cisplatin-augmented cancer stem cells than control mice. Stool analysis indicated nonresistant gut microbial species were disrupted by ABX treatment. Cecal transplants of microbiota derived from control-treated mice was sufficient to ameliorate chemoresistance and prolong survival of ABX-treated mice, indicative of a gut-derived tumor suppressor. Metabolomics analyses identified circulating gut-derived metabolites that were altered by ABX treatment and restored by recolonization, providing candidate metabolites that mediate the cross-talk between the gut microbiome and ovarian cancer. Collectively, these findings indicate that an intact microbiome functions as a tumor suppressor in EOC, and perturbation of the gut microbiota with ABX treatment promotes tumor growth and suppresses cisplatin sensitivity., Significance: Restoration of the gut microbiome, which is disrupted following antibiotic treatment, may help overcome platinum resistance in patients with epithelial ovarian cancer. See related commentary by Hawkins and Nephew, p. 4511., (©2022 American Association for Cancer Research.)
- Published
- 2022
- Full Text
- View/download PDF
49. Distinct Cell Adhesion Signature Defines Glioblastoma Myeloid-Derived Suppressor Cell Subsets.
- Author
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Bayik D, Bartels CF, Lovrenert K, Watson DC, Zhang D, Kay K, Lee J, Lauko A, Johnson S, Lo A, Silver DJ, McGraw M, Grabowski M, Mohammadi AM, Veglia F, Fan Y, Vogelbaum MA, Scacheri P, and Lathia JD
- Subjects
- Animals, Humans, Mice, Integrin beta1 metabolism, Tumor Microenvironment, Cell Adhesion, Glioblastoma metabolism, Glioblastoma pathology, Myeloid-Derived Suppressor Cells pathology
- Abstract
In multiple types of cancer, an increased frequency in myeloid-derived suppressor cells (MDSC) is associated with worse outcomes and poor therapeutic response. In the glioblastoma (GBM) microenvironment, monocytic (m) MDSCs represent the predominant subset. However, the molecular basis of mMDSC enrichment in the tumor microenvironment compared with granulocytic (g) MDSCs has yet to be determined. Here we performed the first broad epigenetic profiling of MDSC subsets to define underlying cell-intrinsic differences in behavior and found that enhanced gene accessibility of cell adhesion programs in mMDSCs is linked to their tumor-accelerating ability in GBM models upon adoptive transfer. Mouse and human mMDSCs expressed higher levels of integrin β1 and dipeptidyl peptidase-4 (DPP-4) compared with gMDSCs as part of an enhanced cell adhesion signature. Integrin β1 blockade abrogated the tumor-promoting phenotype of mMDSCs and altered the immune profile in the tumor microenvironment, whereas treatment with a DPP-4 inhibitor extended survival in preclinical GBM models. Targeting DPP-4 in mMDSCs reduced pERK signaling and their migration towards tumor cells. These findings uncover a fundamental difference in the molecular basis of MDSC subsets and suggest that integrin β1 and DPP-4 represent putative immunotherapy targets to attenuate myeloid cell-driven immune suppression in GBM., Significance: Epigenetic profiling uncovers cell adhesion programming as a regulator of the tumor-promoting functions of monocytic myeloid-derived suppressor cells in glioblastoma, identifying therapeutic targets that modulate the immune response and suppress tumor growth., (©2022 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2022
- Full Text
- View/download PDF
50. VRK1 Is a Synthetic-Lethal Target in VRK2-Deficient Glioblastoma.
- Author
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Shields JA, Meier SR, Bandi M, Mulkearns-Hubert EE, Hajdari N, Ferdinez MD, Engel JL, Silver DJ, Shen B, Zhang W, Hubert CG, Mitchell K, Shakya S, Zhao SC, Bejnood A, Zhang M, Tjin Tham Sjin R, Wilker E, Lathia JD, Andersen JN, Chen Y, Li F, Weber B, Huang A, and Emmanuel N
- Subjects
- Humans, Apoptosis, Cell Line, Tumor, G2 Phase Cell Cycle Checkpoints, Vaccinia virus, Phosphorylation, Protein Serine-Threonine Kinases, Glioblastoma
- Abstract
Synthetic lethality is a genetic interaction that results in cell death when two genetic deficiencies co-occur but not when either deficiency occurs alone, which can be co-opted for cancer therapeutics. Pairs of paralog genes are among the most straightforward potential synthetic-lethal interactions by virtue of their redundant functions. Here, we demonstrate a paralog-based synthetic lethality by targeting vaccinia-related kinase 1 (VRK1) in glioblastoma (GBM) deficient of VRK2, which is silenced by promoter methylation in approximately two thirds of GBM. Genetic knockdown of VRK1 in VRK2-null or VRK2-methylated cells resulted in decreased activity of the downstream substrate barrier to autointegration factor (BAF), a regulator of post-mitotic nuclear envelope formation. Reduced BAF activity following VRK1 knockdown caused nuclear lobulation, blebbing, and micronucleation, which subsequently resulted in G2-M arrest and DNA damage. The VRK1-VRK2 synthetic-lethal interaction was dependent on VRK1 kinase activity and was rescued by ectopic expression of VRK2. In VRK2-methylated GBM cell line-derived xenograft and patient-derived xenograft models, knockdown of VRK1 led to robust tumor growth inhibition. These results indicate that inhibiting VRK1 kinase activity could be a viable therapeutic strategy in VRK2-methylated GBM., Significance: A paralog synthetic-lethal interaction between VRK1 and VRK2 sensitizes VRK2-methylated glioblastoma to perturbation of VRK1 kinase activity, supporting VRK1 as a drug discovery target in this disease., (©2022 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2022
- Full Text
- View/download PDF
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