24 results on '"Cynthia, Loomis"'
Search Results
2. Data from Genetic Suppression of Inflammation Blocks the Tumor-Promoting Effects of TGF-β in Gastric Tissue
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Daniel B. Rifkin, Michael Cammer, Cynthia Loomis, Kyuichi Kadota, Kotaro Shibahara, Victoria Fang, Masahito Horiguchi, and Mitsuhiko Ota
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The contributions of TGF-β signaling to cancer are complex but involve the inflammatory microenvironment as well as cancer cells themselves. In mice encoding a TGF-β mutant that precludes its binding to the latent TGF-β binding protein (Tgfb1−/C33S), we observed multiorgan inflammation and an elevated incidence of various types of gastrointestinal solid tumors due to impaired conversion of latent to active TGF-β1. By genetically eliminating activators of latent TGF-β1, we further lowered the amount of TGF-β, which enhanced tumor frequency and multiorgan inflammation. This model system was used to further investigate the relative contribution of TGF-β1 to lymphocyte-mediated inflammation in gastrointestinal tumorigenesis. Toward this end, we generated Tgfb1−/C33S;Rag2−/− mice that lacked adaptive immune function, which eliminated tumor production. Analysis of tissue from Tgfb1−/C33S mice indicated decreased levels of P-Smad3 compared with wild-type animals, whereas tissue from Tgfb1−/C33S;Rag2−/− mice had normal P-Smad3 levels. Inhibiting the inflammatory response normalized levels of interleukin (IL)-1β and IL-6 and reduced tumor cell proliferation. In addition, Tgfb1−/C33S;Rag2−/− mice exhibited reduced paracrine signaling in the epithelia, mediated by hepatocyte growth factor produced by gastric stroma. Together, our results indicate that many of the responses of the gastric tissue associated with decreased TGF-β1 may be directly or indirectly affected by inflammatory processes, which accompany loss of TGF-β1, rather than a direct effect of loss of the cytokine. Cancer Res; 74(9); 2642–51. ©2014 AACR.
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- 2023
3. Supplementary Figure Legends, Tables 1 - 2 from Genetic Suppression of Inflammation Blocks the Tumor-Promoting Effects of TGF-β in Gastric Tissue
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Daniel B. Rifkin, Michael Cammer, Cynthia Loomis, Kyuichi Kadota, Kotaro Shibahara, Victoria Fang, Masahito Horiguchi, and Mitsuhiko Ota
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PDF file - 108KB, Supplementary Table 1. Primer List. Supplementary Table 2. Distribution of Tgfb1 and Rag2 Genes.
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- 2023
4. A comparative study ofin vitroair-liquid interface culture models of the human airway epithelium evaluating cellular heterogeneity and gene expression at single cell resolution
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Rachel A. Prescott, Alec P. Pankow, Maren de Vries, Keaton Crosse, Roosheel S. Patel, Mark Alu, Cynthia Loomis, Victor Torres, Sergei Koralov, Ellie Ivanova, Meike Dittmann, and Brad R. Rosenberg
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The airway epithelium is composed of diverse cell types with specialized functions that mediate homeostasis and protect against respiratory pathogens. Human airway epithelial cultures at air-liquid interface (HAE) are a physiologically relevantin vitromodel of this heterogeneous tissue, enabling numerous studies of airway disease1–7. HAE cultures are classically derived from primary epithelial cells, the relatively limited passage capacity of which can limit experimental methods and study designs. BCi-NS1.1, a previously described and widely used basal cell line engineered to express hTERT, exhibits extended passage lifespan while retaining capacity for differentiation to HAE5. However, gene expression and innate immune function in HAE derived from BCi-NS1.1 versus primary cells have not been fully characterized. Here, combining single cell RNA-Seq (scRNA-Seq), immunohistochemistry, and functional experimentation, we confirm at high resolution that BCi-NS1.1 and primary HAE cultures are largely similar in morphology, cell type composition, and overall transcriptional patterns. While we observed cell-type specific expression differences of several interferon stimulated genes in BCi-NS1.1 HAE cultures, we did not observe significant differences in susceptibility to infection with influenza A virus andStaphylococcus aureus. Taken together, our results further support BCi-NS1.1-derived HAE cultures as a valuable tool for the study of airway infectious disease.
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- 2023
5. Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment
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Gregor Werba, Daniel Weissinger, Emily A. Kawaler, Ende Zhao, Despoina Kalfakakou, Surajit Dhara, Lidong Wang, Heather B. Lim, Grace Oh, Xiaohong Jing, Nina Beri, Lauren Khanna, Tamas Gonda, Paul Oberstein, Cristina Hajdu, Cynthia Loomis, Adriana Heguy, Mara H. Sherman, Amanda W. Lund, Theodore H. Welling, Igor Dolgalev, Aristotelis Tsirigos, and Diane M. Simeone
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Multidisciplinary ,General Physics and Astronomy ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology - Abstract
The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression; however, in-depth single cell characterization of the PDAC TME and its role in response to therapy is lacking. Here, we perform single-cell RNA sequencing on freshly collected human PDAC samples either before or after chemotherapy. Overall, we find a heterogeneous mixture of basal and classical cancer cell subtypes, along with distinct cancer-associated fibroblast and macrophage subpopulations. Strikingly, classical and basal-like cancer cells exhibit similar transcriptional responses to chemotherapy and do not demonstrate a shift towards a basal-like transcriptional program among treated samples. We observe decreased ligand-receptor interactions in treated samples, particularly between TIGIT on CD8 + T cells and its receptor on cancer cells, and identify TIGIT as the major inhibitory checkpoint molecule of CD8 + T cells. Our results suggest that chemotherapy profoundly impacts the PDAC TME and may promote resistance to immunotherapy.
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- 2023
6. Combined Inhibition of SHP2 and CXCR1/2 Promotes Antitumor T-cell Response in NSCLC
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Argus Athanas, Kwok-Kin Wong, John A Zebala, Carmine Fedele, Han Han, Yuan Hao, Kwan Ho Tang, Kayla Guidry, James G. Christensen, Benjamin G. Neel, Aristotelis Tsirigos, Dean Y. Maeda, Alireza Khodadadi-Jamayran, Cynthia Loomis, Ting Chen, Peter D. Olson, Shuai Li, and Jayu Jen
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Male ,MAPK/ERK pathway ,Lung Neoplasms ,Antineoplastic Agents ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,medicine.disease_cause ,Receptors, Interleukin-8B ,Article ,CCL5 ,Mice ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Tumor Microenvironment ,medicine ,Animals ,Humans ,CXCL10 ,Cytotoxic T cell ,Enzyme Inhibitors ,Receptor ,Tumor microenvironment ,Chemistry ,Xenograft Model Antitumor Assays ,respiratory tract diseases ,Mice, Inbred C57BL ,Oncology ,Cancer research ,KRAS ,CD8 - Abstract
SHP2 inhibitors (SHP2i) alone and in various combinations are being tested in multiple tumors with overactivation of the RAS/ERK pathway. SHP2 plays critical roles in normal cell signaling; hence, SHP2is could influence the tumor microenvironment. We found that SHP2i treatment depleted alveolar and M2-like macrophages, induced tumor-intrinsic CCL5/CXCL10 secretion, and promoted B and T lymphocyte infiltration in Kras- and Egfr-mutant non–small cell lung cancer (NSCLC). However, treatment also increased intratumor granulocytic myeloid-derived suppressor cells (gMDSC) via tumor-intrinsic, NFκB-dependent production of CXCR2 ligands. Other RAS/ERK pathway inhibitors also induced CXCR2 ligands and gMDSC influx in mice, and CXCR2 ligands were induced in tumors from patients on KRASG12C inhibitor trials. Combined SHP2 (SHP099)/CXCR1/2 (SX682) inhibition depleted a specific cluster of S100a8/9hi gMDSCs, generated Klrg1+ CD8+ effector T cells with a strong cytotoxic phenotype but expressing the checkpoint receptor NKG2A, and enhanced survival in Kras- and Egfr-mutant models. Our results argue for testing RAS/ERK pathway/CXCR1/2/NKG2A inhibitor combinations in patients with NSCLC. Significance: Our study shows that inhibiting the SHP2/RAS/ERK pathway triggers NFκB-dependent upregulation of CXCR2 ligands and recruitment of S100A8hi gMDSCs, which suppress T cells. Combining SHP2/CXCR2 inhibitors blocks gMDSC immigration, resulting in enhanced Th1 polarization, induced CD8+KLRG1+ effector T cells with high cytotoxic activity, and improved survival in multiple NSCLC models. This article is highlighted in the In This Issue feature, p. 1
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- 2021
7. A neonatal mouse model characterizes transmissibility of SARS-CoV-2 variants and reveals a role for ORF8
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Bruno A. Rodriguez-Rodriguez, Grace O. Ciabattoni, Ralf Duerr, Ana M Valero-Jimenez, Stephen T. Yeung, Keaton M. Crosse, Austin R. Schinlever, Lucie Bernard-Raichon, Joaquin J. Rodriguez-Galvan, Marisa E. McGrath, Sanjay Vashee, Yong Xue, Cynthia Loomis, Kamal M. Khanna, Kenneth Cadwell, Ludovic Desvignes, Matthew F. Frieman, Mila B Ortigoza, and Meike Dittmann
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Multidisciplinary ,General Physics and Astronomy ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology ,Article - Abstract
Small animal models have been a challenge for the study of SARS-CoV-2 transmission, with most investigators using golden hamsters or ferrets1, 2. Mice have the advantages of low cost, wide availability, less regulatory and husbandry challenges, and the existence of a versatile reagent and genetic toolbox. However, adult mice do not robustly transmit SARS-CoV-23. Here we establish a model based on neonatal mice that allows for transmission of clinical SARS-CoV-2 isolates. We characterize tropism, respiratory tract replication and transmission of ancestral WA-1 compared to variants Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Omicron BA.1 and Omicron BQ.1.1. We identify inter-variant differences in timing and magnitude of infectious particle shedding from index mice, both of which shape transmission to contact mice. Furthermore, we characterize two recombinant SARS-CoV-2 lacking either the ORF6 or ORF8 host antagonists. The removal of ORF8 shifts viral replication towards the lower respiratory tract, resulting in significantly delayed and reduced transmission in our model. Our results demonstrate the potential of our neonatal mouse model to characterize viral and host determinants of SARS-CoV-2 transmission, while revealing for the first time a role for an accessory protein in this context.
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- 2022
8. Interleukin-17 governs hypoxic adaptation of injured epithelium
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Piotr Konieczny, Yue Xing, Ikjot Sidhu, Ipsita Subudhi, Kody P. Mansfield, Brandon Hsieh, Douglas E. Biancur, Samantha B. Larsen, Michael Cammer, Dongqing Li, Ning Xu Landén, Cynthia Loomis, Adriana Heguy, Anastasia N. Tikhonova, Aristotelis Tsirigos, and Shruti Naik
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Wound Healing ,Multidisciplinary ,Receptors, Interleukin-17 ,Gene Expression Profiling ,T-Lymphocytes ,Interleukin-17 ,Epithelial Cells ,Hypoxia-Inducible Factor 1, alpha Subunit ,Epithelium ,Article ,Mice ,Animals ,Humans ,Single-Cell Analysis ,Hypoxia ,Signal Transduction - Abstract
INTRODUCTION: Injury compromises our epithelial barriers, leaving them vulnerable to external threats. Organismal survival thus impinges on rapid barrier re-establishment after damage. Immunocompromised individuals and immunodeficient animals have profound defects in epithelial repair. However, the precise mechanisms and consequences of immune-epithelial cross-talk after injury remain incompletely defined. RATIONALE: Epithelial repair requires cellular adaptation to the hypoxic wound microenvironment through evolutionarily conserved hypoxia-inducible factors (HIFs). This response has long been thought to depend upon epithelial cell-autonomous sensing of oxygen deprivation and responsiveness through HIFs. However, whether and how supportive microenvironmental signals from immune cells intersect with ancient hypoxia responses during epithelial repair have yet to be explored. To address these questions, we were drawn to the skin, a primary epithelial barrier that is surveilled by immune cells and has evolved sophisticated repair mechanisms. RESULTS: Using unbiased profiling of repair-associated lymphocytes, we uncovered the enrichment of heterogeneous populations of type 17 lymphocytes. Homozygous Rorgt-EGFP (GFI-KI) mice deficient in RORγt(+) cells exhibited a significant defect in epithelial migration and wound re-epithelialization. After damage, we observed a rapid local expansion of preexisting skin-resident RORγt(+) cells that was sufficient to drive repair. Of the myriad wound RORγt(+) populations, spatial transcriptomics and functional studies revealed that innate-like γδ T cells directed tissue repair by localizing to the wound front and boosting epithelial migration. These cells dominantly produced IL-17A/F in the wound microenvironment, which signaled directly to epithelia through IL-17RC to induce a migratory program. Comparative spatial transcriptomics of RORγt(+) cell-deficient and wild-type (WT) wound edges revealed differences in HIF1α signaling. WT migrating epithelia had robust nuclear HIF1α activation that was notably missing from RORγt(+) cell– and epithelial IL-17RC–deficient (Il17rc(EKO)) animals. Accordingly, epithelial-specific loss of HIF1α (Hif1a(EKO)) phenocopied the wound-healing defect of GFP-KI and Il17rc(EKO) mice. However, in contrast to GFP-KI wounds, recombinant IL-17A was unable to augment repair in Hif1a(EKO) mice, underscoring the necessity of this transcriptional effector mediating re-epithelialization downstream of IL-17A signaling. RORγt(+) cell–deficient and control animals had comparable levels of wound hypoxia, indicating that the failure of RORγt(+) cell–deficient animals to induce HIF1α was independent of oxygen sensing. Instead, IL-17A was sufficient to activate epithelial HIF1α both in vivo and in epithelial organoids. IL-17RC signaling rapidly induced activation of both ERK and AKT, which augmented HIF1α protein and transcript levels, but not stability, through mammalian target of rapamycin (mTOR). Acute hypoxia potently activated epithelial HIF1α in vitro, and this response was further boosted by IL-17A. By contrast, we uncovered a striking loss of mTOR and HIF1α in chronic hypoxia. Exogenous IL-17A rescued mTOR, and consequently HIF1α, under conditions of chronic hypoxia, indicating that IL-17A acts as a second signal to enable cell adaptation to low-oxygen environments. IL-17A induced a transcriptional and functional program of glycolytic metabolism in epithelia, which was dependent upon mTOR and HIF1α. The IL-17A-HIF1α-dependent program of glycolysis fueled epithelial migration, and pharmacological inhibition of glycolysis impaired wound re-epithelialization. CONCLUSION: Our findings upend a long-held view that hypoxia is sufficient to cell-autonomously induce HIF1α-mediated metabolic remodeling. We illustrate that IL-17A supplied by RORγt(+) γδ T cells is necessary for optimal HIF1α activation in the wound-edge epithelium. The IL-17A-HIF1α axis directed the metabolic rewiring of damaged epithelium toward a program of glycolysis to fuel migration. HIF1α and glycolysis are drivers of tumor progression and metastasis, raising the possibility that IL-17A or other immune-derived signals could drive these pathways in cancer. IL-17A is also central to the pathology of many autoimmune conditions, including psoriasis and inflammatory bowel disease. Thus, the IL-17A–HIF1α axis unveiled by our study may provide therapeutic opportunities for a range of epithelial inflammatory and metastatic diseases.
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- 2022
9. MAVS signaling is required for clearance of chikungunya heart infection and prevention of chronic inflammation in vascular tissue
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Maria G. Noval, Sophie N. Spector, Eric Bartnicki, Franco Izzo, Navneet Narula, Stephen T. Yeung, Payal Damani-Yokota, M. Zahidunnabi Dewan, Valeria Mezzano, Bruno A. Rodriguez-Rodriguez, Cynthia Loomis, Kamal M. Khanna, and Kenneth A. Stapleford
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Chikungunya virus (CHIKV) infection has been associated with severe cardiac manifestations, yet, how CHIKV infection leads to heart disease remains unknown. Here, we leveraged both mouse models and human primary cells to define the mechanisms of CHIKV heart infection. We found that CHIKV actively replicates in cardiac fibroblasts and is cleared without significant tissue damage through the induction of a local type-I interferon response from both infected and non-infected cardiac cells. Importantly, signaling through the mitochondrial antiviral-signaling protein (MAVS) is required for viral clearance from the heart. In the absence of MAVS, persistent infection leads to focal myocarditis and major vessel vasculitis persisting for up to 60 days post-infection, suggesting CHIKV can lead to vascular inflammation and potential long-lasting cardiovascular complications. This study provides a model of CHIKV cardiac infection and mechanistic insight into CHIKV-induced heart disease, underscoring the importance of monitoring cardiac function in patients with CHIKV infections.
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- 2022
10. Single-Cell RNA Sequencing Reveals the Effects of Chemotherapy on Human Pancreatic Adenocarcinoma and its Tumor Microenvironment
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Gregor Werba, Daniel Weissinger, Emily A. Kawaler, Ende Zhao, Despoina Kalfakakou, Surajit Dhara, Grace Oh, Xiaohong Jing, Nina Beri, Lauren Khanna, Tamas Gonda, Paul Oberstein, Cristina Hajdu, Cynthia Loomis, Adriana Heguy, Mara H. Sherman, Amanda W. Lund, Theodore H. Welling, Igor Dolgalev, Aristotelis Tsirigos, and Diane M. Simeone
- Abstract
The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression; however, in-depth single cell characterization of the PDAC TME and its role in response to therapy is lacking. We performed single-cell RNA sequencing on freshly collected human PDAC samples either before or after chemotherapy. Overall, we found a heterogeneous mixture of basal and classical cancer cell subtypes, along with distinct cancer-associated fibroblast and macrophage subpopulations. Strikingly, classical and basal-like cancer cells exhibited similar transcriptional responses to chemotherapy, and did not demonstrate a shift towards a basal-like transcriptional program among treated samples. We observed decreased ligand-receptor interactions in treated samples, particularly TIGIT on CD8+ T cells and its receptor on cancer cells, and identified TIGIT as the major inhibitory checkpoint molecule of CD8+ T cells. Our results suggest that chemotherapy profoundly impacts the PDAC TME and may promote resistance to immunotherapy.
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- 2022
11. Genetically Defined, Syngeneic Organoid Platform for Developing Combination Therapies for Ovarian Cancer
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Wei Wei, Connor Foster, Benjamin G. Neel, Douglas A. Levine, Narciso Olvera, Fanny Dao, Robert A. Weinberg, Shengqing Gu, Shuang Zhang, Sonia Iyer, Hao Ran, Igor Dolgalev, and Cynthia Loomis
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0301 basic medicine ,Chemokine ,endocrine system diseases ,medicine.medical_treatment ,Mice, Transgenic ,Biology ,medicine.disease_cause ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Tumor Microenvironment ,medicine ,Organoid ,Animals ,Fallopian Tube Neoplasms ,Humans ,CRISPR ,Ovarian Neoplasms ,Immunotherapy ,medicine.disease ,Cystadenocarcinoma, Serous ,3. Good health ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,Disease Models, Animal ,Serous fluid ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Female ,KRAS ,Ovarian cancer - Abstract
The paucity of genetically informed, immunocompetent tumor models impedes evaluation of conventional, targeted, and immune therapies. By engineering mouse fallopian tube epithelial organoids using lentiviral gene transduction and/or CRISPR/Cas9 mutagenesis, we generated multiple high-grade serous tubo-ovarian cancer (HGSC) models exhibiting mutational combinations seen in patients with HGSC. Detailed analysis of homologous recombination (HR)–proficient (Trp53−/−;Ccne1OE;Akt2OE;KrasOE), HR-deficient (Trp53−/−;Brca1−/−;MycOE), and unclassified (Trp53−/−;Pten−/−;Nf1−/−) organoids revealed differences in in vitro properties (proliferation, differentiation, and “secretome”), copy-number aberrations, and tumorigenicity. Tumorigenic organoids had variable sensitivity to HGSC chemotherapeutics, and evoked distinct immune microenvironments that could be modulated by neutralizing organoid-produced chemokines/cytokines. These findings enabled development of a chemotherapy/immunotherapy regimen that yielded durable, T cell–dependent responses in Trp53−/−;Ccne1OE;Akt2OE;Kras HGSC; in contrast, Trp53−/−;Pten−/−;Nf1−/− tumors failed to respond. Mouse and human HGSC models showed genotype-dependent similarities in chemosensitivity, secretome, and immune microenvironment. Genotype-informed, syngeneic organoid models could provide a platform for the rapid evaluation of tumor biology and therapeutics. Significance: The lack of genetically informed, diverse, immunocompetent models poses a major barrier to therapeutic development for many malignancies. Using engineered fallopian tube organoids to study the cell-autonomous and cell-nonautonomous effects of specific combinations of mutations found in HGSC, we suggest an effective combination treatment for the currently intractable CCNE1-amplified subgroup. This article is highlighted in the In This Issue feature, p. 211
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- 2021
12. Sindbis Virus with Anti-OX40 Overcomes the Immunosuppressive Tumor Microenvironment of Low-Immunogenic Tumors
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Cynthia Loomis, Alicia Hurtado, Daniel Meruelo, Silvana Opp, Iris Scherwitzl, Christine Pampeno, Kasthuri Kannan, and Minjun Yu
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0301 basic medicine ,Cancer Research ,Sindbis virus ,medicine.medical_treatment ,anti-OX40 ,alpha-virus immunotherapy ,anti-tumor immunity ,lcsh:RC254-282 ,Article ,oncolytic virus anti-OX40 combination therapy ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Antigen ,Cancer immunotherapy ,cancer immunity ,Sindbis ,Medicine ,Pharmacology (medical) ,Tumor microenvironment ,biology ,Effector ,business.industry ,Immunotherapy ,biology.organism_classification ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Oncolytic virus ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,business - Abstract
Despite remarkable responses to cancer immunotherapy in a subset of patients, many patients remain resistant to therapies. It is now clear that elevated levels of tumor-infiltrating T cells as well as a systemic anti-tumor immune response are requirements for successful immunotherapies. However, the tumor microenvironment imposes an additional resistance mechanism to immunotherapy. We have developed a practical and improved strategy for cancer immunotherapy using an oncolytic virus and anti-OX40. This strategy takes advantage of a preexisting T cell immune repertoire in vivo, removing the need to know about present tumor antigens. We have shown in this study that the replication-deficient oncolytic Sindbis virus vector expressing interleukin-12 (IL-12) (SV.IL12) activates immune-mediated tumor killing by inducing OX40 expression on CD4 T cells, allowing the full potential of the agonistic anti-OX40 antibody. The combination of SV.IL12 with anti-OX40 markedly changes the transcriptome signature and metabolic program of T cells, driving the development of highly activated terminally differentiated effector T cells. These metabolically reprogrammed T cells demonstrate enhanced tumor infiltration capacity as well as anti-tumor activity capable of overcoming the repressive tumor microenvironment. Our findings identify SV.IL12 in combination with anti-OX40 to be a novel and potent therapeutic strategy that can cure multiple types of low-immunogenic solid tumors., Graphical Abstract, Despite remarkable responses to cancer immunotherapy, many patients remain resistant to therapies. The harsh tumor microenvironment blocks tumor penetration, impairing the cancer killing functions of the immune system. In this study, the authors show that the combination of an oncolytic virus and anti-OX40 antibody can successfully cure multiple tumors by overcoming this resistance.
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- 2020
13. Abstract PR010: Single-cell sequencing elucidates the effects of chemotherapy on cancer cell heterogeneity and the tumor microenvironment of human pancreatic adenocarcinoma
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Daniel Weissinger, Emily A. Kawaler, Gregor Werba, Ende Zhao, Despoina Kalfakakou, Surajit Dhara, Grace Oh, Xiaohong Jing, Nina Beri, Lauren Khanna, Tamas Gonda, Paul E. Oberstein, Cristina Hajdu, Cynthia Loomis, Adriana Heguy, Mara H. Sherman, Amanda W. Lund, Theodore H. Welling, Igor Dolgalev, Aristotelis Tsirigos, and Diane M. Simeone
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Cancer Research ,Oncology - Abstract
The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression. Improving our understanding of the PDAC TME and its role in response to therapy via in-depth single cell characterization will have broad clinical implications for biomarker development and therapeutic design. In this study, we performed single-cell RNA sequencing on freshly collected human PDAC samples of primary (n=16) or metastatic (n=11) origin, either before (n=20) or after (n=7) chemotherapy. We found a heterogeneous mixture of basal and classical Moffitt cancer cell subtypes in all samples, along with distinct cancer-associated fibroblast (CAF) and tumor-associated macrophage (TAM) subpopulations. We identified the major CAF subpopulations as inflammatory CAFs (iCAFs) and myofibroblastic CAFs (myCAFs); within these subpopulations were a very few cells expressing immunogenic features which have previously been associated with antigen presenting CAFs (apCAFs). Tumor-associated macrophages (TAMs) could be categorized into two major subpopulations, C1QC+ TAMs or SPP1+ TAMs, each with distinct functional characteristics. For example, phagocytosis-associated gene sets were enriched in C1QC+ TAMs, while angiogenesis-associated gene sets were enriched in SPP1+ TAMs. Comparison of naïve and chemotherapy treated primary PDAC samples revealed that classical and basal-like cancer cells exhibited similar transcriptional responses to chemotherapy; this contrasts with some previous reports which posited a shift towards a basal-like transcriptional program among treated samples. We further noted that treated samples evinced fewer ligand-receptor interactions, particularly between TIGIT on CD8+ T cells and its ligand on cancer cells. We also identified TIGIT, not PD1, as the major inhibitory checkpoint molecule of CD8+ T cells in the PDAC TME. Altogether, our results suggest that chemotherapy impacts the PDAC TME and may further reduce response to immunotherapy. Citation Format: Daniel Weissinger, Emily A. Kawaler, Gregor Werba, Ende Zhao, Despoina Kalfakakou, Surajit Dhara, Grace Oh, Xiaohong Jing, Nina Beri, Lauren Khanna, Tamas Gonda, Paul E. Oberstein, Cristina Hajdu, Cynthia Loomis, Adriana Heguy, Mara H. Sherman, Amanda W. Lund, Theodore H. Welling, Igor Dolgalev, Aristotelis Tsirigos, Diane M. Simeone. Single-cell sequencing elucidates the effects of chemotherapy on cancer cell heterogeneity and the tumor microenvironment of human pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR010.
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- 2022
14. Decreased production of epithelial-derived antimicrobial molecules at mucosal barriers during early life
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Debby Bogaert, Kristen L. Lokken-Toyli, Bo Shopsin, Kirsten Kuipers, Rachel A. Martel, Jeffrey N. Weiser, Wouter A. A. de Steenhuijsen Piters, Cynthia Loomis, and Tonia Zangari
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Immunology ,medicine.disease_cause ,Microbiology ,chemistry.chemical_compound ,Mice ,Anti-Infective Agents ,Streptococcus pneumoniae ,medicine ,Immunology and Allergy ,Animals ,Humans ,Immunity, Mucosal ,Disease Resistance ,Gastrointestinal tract ,Mucous Membrane ,biology ,Lactoferrin ,Age Factors ,Epithelial Cells ,Immunohistochemistry ,Small intestine ,Immunity, Innate ,medicine.anatomical_structure ,chemistry ,Gene Expression Regulation ,Staphylococcus aureus ,Organ Specificity ,biology.protein ,Muramidase ,Lysozyme ,Polymeric immunoglobulin receptor ,Antimicrobial Peptides ,Biomarkers ,Respiratory tract - Abstract
Young age is a risk factor for respiratory and gastrointestinal infections. Here, we compared infant and adult mice to identify agedependent mechanisms that drive susceptibility to mucosal infections during early life. Transcriptional profiling of the upper respiratory tract (URT) epithelium revealed significant dampening of early life innate mucosal defenses. Epithelial-mediatedproduction of the most abundant antimicrobial molecules, lysozyme, and lactoferrin, and the polymeric immunoglobulin receptor (pIgR), responsible for IgA transcytosis, was expressed in an age-dependent manner. This was attributed to delayed functional development of serous cells. Absence of epithelial-derived lysozyme and the pIgR was also observed in the small intestine during early life. Infection of infant mice with lysozyme-susceptible strains of Streptococcus pneumoniae or Staphylococcus aureus in theURT or gastrointestinal tract, respectively, demonstrated an age-dependent regulation of lysozyme enzymatic activity. Lysozyme derived from maternal milk partially compensated for the reduction in URT lysozyme activity of infant mice. Similar to our observations in mice, expression of lysozyme and the pIgR in nasopharyngeal samples collected from healthy human infants during the first year of life followed an age-dependent regulation. Thus, a global pattern of reduced antimicrobial and IgA-mediated defenses may contribute to increased susceptibility of young children to mucosal infections.
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- 2021
15. Systems‐Based Analysis of the Pancreatic Cancer‐Specific Glycome Reveals ST6GAL1 as a Driver of Human and Murine Disease
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Emily A. Vucic, Gillian G. Baptiste, Cristina H. Hajdu, Lara K. Mahal, Dafna Bar Sagi, Cynthia Loomis, Emma Kurz, Shuhui Chen, and Praveen Agarwal
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business.industry ,Pancreatic cancer ,Genetics ,Cancer research ,medicine ,Disease ,medicine.disease ,business ,Molecular Biology ,Biochemistry ,Glycome ,Biotechnology - Published
- 2021
16. Lower airway dysbiosis affects lung cancer progression
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Daniel H. Sterman, Jose C. Clemente, Peter Meyn, Sergei B. Koralov, Kevin Felner, R. Schluger, Luisannay Perez, Linchen He, Adriana Heguy, J. Carpenito, Richard Bonneau, Mariam El-Ashmawy, Yonghua Li, B. Franca, William N. Rom, Ting An Yie, Imran Sulaiman, James T. Morton, Anastasia Maria Zavitsanou, Valeria Mezzano, Benjamin G. Wu, Katherine Gershner, Cynthia Loomis, Robert L. Smith, Samaan Rafeq, Andre L. Moreira, Gaetane Michaud, Huilin Li, Leopoldo N. Segal, Harald Sauthoff, William Moore, Tadasu Iizumi, Ray Pillai, Aristotelis Tsirigos, Harvey I. Pass, Jamie L. Bessich, Thales Papagiannakopoulos, E. Olsen, Kwok-Kin Wong, Jun Chieh J. Tsay, Michelle H. Badri, and Nan Shen
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0301 basic medicine ,Lung Neoplasms ,medicine.medical_treatment ,New York ,Mice, Transgenic ,Adenocarcinoma ,Gut flora ,medicine.disease_cause ,Article ,Cohort Studies ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Animals ,Humans ,Neoplasm Metastasis ,Lung cancer ,Lung ,Neoplasm Staging ,Proportional Hazards Models ,biology ,business.industry ,Microbiota ,Cancer ,Immunotherapy ,respiratory system ,medicine.disease ,biology.organism_classification ,Survival Analysis ,respiratory tract diseases ,Gastrointestinal Microbiome ,Disease Models, Animal ,030104 developmental biology ,Oncology ,Tumor progression ,030220 oncology & carcinogenesis ,Immunology ,Disease Progression ,Dysbiosis ,Female ,Carcinogenesis ,business - Abstract
In lung cancer, enrichment of the lower airway microbiota with oral commensals commonly occurs, and ex vivo models support that some of these bacteria can trigger host transcriptomic signatures associated with carcinogenesis. Here, we show that this lower airway dysbiotic signature was more prevalent in the stage IIIB–IV tumor–node–metastasis lung cancer group and is associated with poor prognosis, as shown by decreased survival among subjects with early-stage disease (I–IIIA) and worse tumor progression as measured by RECIST scores among subjects with stage IIIB–IV disease. In addition, this lower airway microbiota signature was associated with upregulation of the IL17, PI3K, MAPK, and ERK pathways in airway transcriptome, and we identified Veillonella parvula as the most abundant taxon driving this association. In a KP lung cancer model, lower airway dysbiosis with V. parvula led to decreased survival, increased tumor burden, IL17 inflammatory phenotype, and activation of checkpoint inhibitor markers. Significance: Multiple lines of investigation have shown that the gut microbiota affects host immune response to immunotherapy in cancer. Here, we support that the local airway microbiota modulates the host immune tone in lung cancer, affecting tumor progression and prognosis. See related commentary by Zitvogel and Kroemer, p. 224. This article is highlighted in the In This Issue feature, p. 211
- Published
- 2020
17. Episodic Aspiration with Oral Commensals Induces a MyD88-dependent, Pulmonary T-Helper Cell Type 17 Response that Mitigates Susceptibility to
- Author
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Benjamin G, Wu, Imran, Sulaiman, Jun-Chieh J, Tsay, Luisanny, Perez, Brendan, Franca, Yonghua, Li, Jing, Wang, Amber N, Gonzalez, Mariam, El-Ashmawy, Joseph, Carpenito, Evan, Olsen, Maya, Sauthoff, Kevin, Yie, Xiuxiu, Liu, Nan, Shen, Jose C, Clemente, Bianca, Kapoor, Tonia, Zangari, Valeria, Mezzano, Cynthia, Loomis, Michael D, Weiden, Sergei B, Koralov, Jeanine, D'Armiento, Sunil K, Ahuja, Xue-Ru, Wu, Jeffrey N, Weiser, and Leopoldo N, Segal
- Subjects
Editorials ,Streptococcus mitis ,Pneumococcal Infections ,Mice, Inbred C57BL ,Veillonella ,Disease Models, Animal ,Mice ,Streptococcus pneumoniae ,Myeloid Differentiation Factor 88 ,Animals ,Humans ,Th17 Cells ,Female ,Prevotella melaninogenica - Published
- 2020
18. Ethylene source attribution modeling in the Greater Houston area
- Author
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Gregory Stella, Dennis McNally, and Cynthia Loomis
- Subjects
Atmospheric Science ,Ethylene ,010504 meteorology & atmospheric sciences ,010501 environmental sciences ,01 natural sciences ,Pollution ,chemistry.chemical_compound ,chemistry ,Human exposure ,Environmental chemistry ,Natural source ,Environmental science ,Biomass burning ,Waste Management and Disposal ,0105 earth and related environmental sciences ,Exposure assessment - Abstract
Ethylene is a ubiquitous industrial gas that is emitted by a wide variety of biogenic, biomass burning, and anthropogenic sources, so the opportunity for human exposure is widespread. We believe that a comprehensive exposure assessment of ethylene from emissions sources has not specifically been evaluated so this study was conducted to estimate the relative contribution of different sources on atmospheric concentrations in the Greater Houston area. Source attribution modeling shows that when averaged over the full modeling domain, inclusive of industrial, urban, rural and water areas, ethylene concentrations are dominated by natural source emissions (fires and biogenic) with an annual mean of 69% of total ethylene concentration. Of the anthropogenic sources, which account for the remaining 31% of the annual ethylene concentration, the largest contribution was from area/non-road sources (annual mean of 16%) with industrial source (annual mean of 11%) and on-road motor vehicle (annual mean of 4%) sources showing relatively lower concentration contributions.
- Published
- 2017
19. PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer
- Author
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Gillian G. Baptiste, Belen Sundberg, Mirhee Kim, Joshua Leinwand, Zennur Sekendiz, Juan A. Kochen Rossi, Ruben D. Salas, Emma Kurz, Gregor Werba, Sorin A. A. Shadaloey, George Miller, Ruonan Chen, Berk Aykut, Shanmugapriya Selvaraj, Kwan Ho Tang, Miguel Liria, Emma Kruger, Susanna Nguy, Carmine Fedele, Salma Adam, Eric Li, Jason Karlen, Gustavo Sanchez, Dongling Wu, Chandan Buttar, Kwok-Kin Wong, Brian Diskin, Ting Chen, Wei Wang, Mautin Hundeyin, Junjie Wang, Cynthia Loomis, Muhammad Israr Ul Haq, Mohammad Saad Farooq, and Marcelo F. Cassini
- Subjects
0301 basic medicine ,CD4-Positive T-Lymphocytes ,Male ,medicine.medical_treatment ,T cell ,Immunology ,Programmed Cell Death 1 Receptor ,CD8-Positive T-Lymphocytes ,medicine.disease_cause ,B7-H1 Antigen ,03 medical and health sciences ,Interferon-gamma ,Mice ,0302 clinical medicine ,Cancer immunotherapy ,PD-L1 ,Cell Line, Tumor ,medicine ,Immune Tolerance ,Tumor Microenvironment ,Immunology and Allergy ,Animals ,Humans ,biology ,Chemistry ,Effector ,Macrophages ,Cell Differentiation ,Tumor antigen ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Self Tolerance ,Cell culture ,biology.protein ,Female ,Carcinogenesis ,CD8 ,030215 immunology ,Signal Transduction - Abstract
Programmed cell death protein 1 (PD-1) ligation delimits immunogenic responses in T cells. However, the consequences of programmed cell death 1 ligand 1 (PD-L1) ligation in T cells are uncertain. We found that T cell expression of PD-L1 in cancer was regulated by tumor antigen and sterile inflammatory cues. PD-L1+ T cells exerted tumor-promoting tolerance via three distinct mechanisms: (1) binding of PD-L1 induced STAT3-dependent 'back-signaling' in CD4+ T cells, which prevented activation, reduced TH1-polarization and directed TH17-differentiation. PD-L1 signaling also induced an anergic T-bet-IFN-γ- phenotype in CD8+ T cells and was equally suppressive compared to PD-1 signaling; (2) PD-L1+ T cells restrained effector T cells via the canonical PD-L1-PD-1 axis and were sufficient to accelerate tumorigenesis, even in the absence of endogenous PD-L1; (3) PD-L1+ T cells engaged PD-1+ macrophages, inducing an alternative M2-like program, which had crippling effects on adaptive antitumor immunity. Collectively, we demonstrate that PD-L1+ T cells have diverse tolerogenic effects on tumor immunity.
- Published
- 2019
20. Neuraminidase B controls neuraminidase A-dependent mucus production and evasion
- Author
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Jeffrey N. Weiser, Ulrike Binsker, Alexandria J. Hammond, Mila Brum Ortigoza, Surya D. Aggarwal, and Cynthia Loomis
- Subjects
Physiology ,Glycoconjugate ,Artificial Gene Amplification and Extension ,Molecular biology assays and analysis techniques ,Biochemistry ,Polymerase Chain Reaction ,chemistry.chemical_compound ,Lectins ,Medicine and Health Sciences ,Biology (General) ,Pathogen ,chemistry.chemical_classification ,biology ,Organic Compounds ,Monosaccharides ,Animal Models ,respiratory system ,Body Fluids ,Chemistry ,Streptococcus pneumoniae ,medicine.anatomical_structure ,Experimental Organism Systems ,Physical Sciences ,Anatomy ,Research Article ,Glycoside Hydrolases ,QH301-705.5 ,Mucociliary clearance ,Immunology ,Carbohydrates ,Neuraminidase ,Mouse Models ,Microbiology ,Model Organisms ,Bacterial Proteins ,Virology ,Genetics ,medicine ,Animals ,Secretion ,CAT assay ,Molecular Biology ,Organic Chemistry ,Mucin ,Chemical Compounds ,Biology and Life Sciences ,Proteins ,Biological Transport ,RC581-607 ,Mucus ,N-Acetylneuraminic Acid ,Sialic acid ,Mice, Inbred C57BL ,Research and analysis methods ,Enzyme ,Molecular biology techniques ,chemistry ,Sialic Acids ,Animal Studies ,biology.protein ,Parasitology ,Immunologic diseases. Allergy ,Physiological Processes ,Respiratory tract - Abstract
Binding of Streptococcus pneumoniae (Spn) to nasal mucus leads to entrapment and clearance via mucociliary activity during colonization. To identify Spn factors allowing for evasion of mucus binding, we used a solid-phase adherence assay with immobilized mucus of human and murine origin. Spn bound large mucus particles through interactions with carbohydrate moieties. Mutants lacking neuraminidase A (nanA) or neuraminidase B (nanB) showed increased mucus binding that correlated with diminished removal of terminal sialic acid residues on bound mucus. The non-additive activity of the two enzymes raised the question why Spn expresses two neuraminidases and suggested they function in the same pathway. Transcriptional analysis demonstrated expression of nanA depends on the enzymatic function of NanB. As transcription of nanA is increased in the presence of sialic acid, our findings suggest that sialic acid liberated from host glycoconjugates by the secreted enzyme NanB induces the expression of the cell-associated enzyme NanA. The absence of detectable mucus desialylation in the nanA mutant, in which NanB is still expressed, suggests that NanA is responsible for the bulk of the modification of host glycoconjugates. Thus, our studies describe a functional role for NanB in sialic acid sensing in the host. The contribution of the neuraminidases in vivo was then assessed in a murine model of colonization. Although mucus-binding mutants showed an early advantage, this was only observed in a competitive infection, suggesting a complex role of neuraminidases. Histologic examination of the upper respiratory tract demonstrated that Spn stimulates mucus production in a neuraminidase-dependent manner. Thus, an increase production of mucus containing secretions appears to be balanced, in vivo, by decreased mucus binding. We postulate that through the combined activity of its neuraminidases, Spn evades mucus binding and mucociliary clearance, which is needed to counter neuraminidase-mediated stimulation of mucus secretions., Author summary Streptococcus pneumoniae (Spn) is a leading mucosal pathogen, whose host interaction begins with colonization of the upper respiratory tract. While there has been extensive investigation into bacterial interaction with epithelial cells, there is little understanding of bacterial-mucus interactions. Our study used mucus of human and murine origin and a murine model of colonization to study mucus associations involving Spn. The main findings reveal i) the enzymatic activity of Spn’s neuraminidases (NanA and NanB) contribute to mucus evasion through removing terminal sialic acid, ii) the enzymatic activity of NanB controls expression of the main neuraminidase, NanA, and iii) Spn induces sialic acid containing mucus secretions in vivo in a neuraminidase-dependent manner. We postulate that during colonization, neuraminidase-dependent reduction in mucus binding enables evasion of mucociliary clearance, which is necessary to counter neuraminidase-mediated stimulation of mucus secretions. Thus, our study provides new insights into the role of Spn neuraminidases on colonization.
- Published
- 2021
21. Integrated Systems Analysis of the Murine and Human Pancreatic Cancer Glycomes Reveals a Tumor-Promoting Role for ST6GAL1
- Author
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Emma Kurz, Emily A. Vucic, Gillian G. Baptiste, Shuhui Chen, Dafna Bar-Sagi, Praveen Agrawal, Cristina H. Hajdu, Lara K. Mahal, and Cynthia Loomis
- Subjects
Male ,Glycosylation ,Systems Analysis ,Proteome ,ST6KC, ST6GAL1flx/flx ,p48Cre ,LSLKRASG12D ,PDAC, pancreatic ductal adenocarcinoma ,pancreatic cancer ,Pancreatic Intraepithelial Neoplasia ,AIA, Artocarpus integrifolia agglutinin ,LcH, Lens culinaris ,Fucose ,TJA-I, Trichosanthes japonica agglutinin ,chemistry.chemical_compound ,lectin microarray ,MNA-G, Morniga G ,SNA, Sambucus nigra agglutinin ,FUT8, alpha-(1,6)-fucosyltranferase ,LEA, Lycopersicon esculentum agglutinin ,ST6GAL1/2, ST6 beta-galactoside alpha-2,6-sialyltransferase 1/2 ,SLBR-H, siglec-like binding region Streptococcus gordonii strains DL1 ,diCBM40, dimeric carbohydrate-binding module 40 ,beta-D-Galactoside alpha 2-6-Sialyltransferase ,bulk-seq, bulk RNA sequencing ,Tissue microarray ,ST6GAL1 ,General Medicine ,DSA, Datura stramonium agglutinin ,FFPE, formalin-fixed paraffin-embedded ,Gene Expression Regulation, Neoplastic ,MNA-M, Morniga M ,NPA, Narcissus pseudonarcissus agglutinin ,poly-LacNAc, poly-N-acetyllactosamine ,Female ,AOL, Aspergillus oryzae lectin ,GNA, Galanthus nivalis agglutinin ,Carcinoma, Pancreatic Ductal ,Glycan ,GRFT, griffithsin ,PSA, Pisum sativum agglutinin ,KC, p48Cre ,In silico ,MAA, Maackia amurensis agglutinin ,WGA, wheat germ agglutinin ,lectin array ,Biology ,H84T, H84T banana lectin ,MPA, Maclura pomifera agglutinin ,Polysaccharides ,Pancreatic cancer ,TMA, tissue microarray ,medicine ,Animals ,Humans ,Pancreas ,Glycoproteins ,MAL-I, Maackia amurensis lectin-I ,PCA, principal component analysis ,AAL, Aleuria aurantia lectin ,PSL, Polyporus squamosus lectin ,Research ,MGAT3, beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase ,PanIN, pancreatic intraepithelial neoplasia ,Cancer ,PC, principal component ,SK1, Streptococcus sanguinis SK1 ,medicine.disease ,PHA-E, Phaseolus vulgaris lectin E ,N-Acetylneuraminic Acid ,Sialyltransferases ,ST3GAL1/2/3/4/5/6, ST3 beta-galactoside alpha-2,3-sialyltransferase 1/2/3/4/5/6 ,Mice, Inbred C57BL ,Pancreatic Neoplasms ,chemistry ,Cancer research ,biology.protein ,SLBR-N, siglec-like binding region Streptococcus gordonii strains UB10712 - Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. Glycans, such as carbohydrate antigen 19-9, are biomarkers of PDAC and are emerging as important modulators of cancer phenotypes. Herein, we used a systems-based approach integrating glycomic analysis of the well-established KC mouse, which models early events in transformation, and analysis of samples from human pancreatic cancer patients to identify glycans with potential roles in cancer formation. We observed both common and distinct patterns of glycosylation in pancreatic cancer across species. Common alterations included increased levels of α-2,3-sialic acid and α-2,6-sialic acid, bisecting GlcNAc and poly-N-acetyllactosamine. However, core fucose, which was increased in human PDAC, was not seen in the mouse, indicating that not all human glycomic changes are observed in the KC mouse model. In silico analysis of bulk and single-cell sequencing data identified ST6 beta-galactoside alpha-2,6-sialyltransferase 1, which underlies α-2,6-sialic acid, as overexpressed in human PDAC, concordant with histological data showing higher levels of this enzyme at the earliest stages. To test whether ST6 beta-galactoside alpha-2,6-sialyltransferase 1 promotes pancreatic cancer, we created a novel mouse in which a pancreas-specific genetic deletion of this enzyme overlays the KC mouse model. The analysis of our new model showed delayed cancer formation and a significant reduction in fibrosis. Our results highlight the importance of a strategic systems approach to identifying glycans whose functions can be modeled in mouse, a crucial step in the development of therapeutics targeting glycosylation in pancreatic cancer., Graphical Abstract, Highlights • Systems approach shows the glycome of KC mouse only partially overlays human PDAC. • α2,6-Sialylation and ST6GAL1 are upregulated in mouse and human pancreatic cancer. • Pancreas-specific ST6GAL1 KO in KC mouse delays cancer formation. • Results show the importance of identifying glycans that can be modeled in mice., In Brief Pancreatic ductal adenocarcinoma is a leading cause of cancer death. Glycans are emerging as important modulators of cancer phenotypes. Herein, we used a strategic systems-based approach integrating glycomics of the KC mouse, modeling early events in transformation, with human data to identify ST6GAL1 (e.g., α-2,6-sialic acid) as a potential cancer promoter. A pancreas-specific ST6GAL1 KO in the KC mouse delayed cancer formation and reduced fibrosis. Our results highlight the importance of identifying glycans whose functions can be modeled in mice.
- Published
- 2021
22. Extensive Remodeling of the Immune Microenvironment in B Cell Acute Lymphoblastic Leukemia
- Author
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William L. Carroll, Gabriel A. Robbins, Cynthia Loomis, Yuling Dai, Iannis Aifantis, Kathryn G. Roberts, Anastasia N. Tikhonova, Chao Ma, Chunxu Qu, Igor Dolgalev, Nikki A. Evensen, Deqing Pei, Aristotelis Tsirigos, Cheng Cheng, Michael E. Scheurer, Shanmugapriya Selvaraj, Karen R. Rabin, Marla Daves, Audrey Lasry, Charles G. Mullighan, Sheetal Sreeram, Valeria Mezzano, Joanna Pierro, Tiffany Chambers, Weiqiang Chen, Philip J. Lupo, and Matthew T. Witkowski
- Subjects
Adult ,Male ,0301 basic medicine ,Cancer Research ,Adolescent ,Proteome ,medicine.medical_treatment ,Immune microenvironment ,Antineoplastic Agents ,Disease ,Article ,Monocytes ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,Tumor Microenvironment ,medicine ,Animals ,Humans ,RNA-Seq ,Child ,Bone Marrow Transplantation ,Retrospective Studies ,Chemotherapy ,business.industry ,Monocyte ,Infant ,B-cell acute lymphoblastic leukemia ,Prognosis ,Mice, Inbred C57BL ,Survival Rate ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Case-Control Studies ,Child, Preschool ,030220 oncology & carcinogenesis ,Disease remission ,Cancer research ,Female ,Bone marrow ,Neoplasm Recurrence, Local ,Single-Cell Analysis ,business - Abstract
Summary A subset of B cell acute lymphoblastic leukemia (B-ALL) patients will relapse and succumb to therapy-resistant disease. The bone marrow microenvironment may support B-ALL progression and treatment evasion. Utilizing single-cell approaches, we demonstrate B-ALL bone marrow immune microenvironment remodeling upon disease initiation and subsequent re-emergence during conventional chemotherapy. We uncover a role for non-classical monocytes in B-ALL survival, and demonstrate monocyte abundance at B-ALL diagnosis is predictive of pediatric and adult B-ALL patient survival. We show that human B-ALL blasts alter a vascularized microenvironment promoting monocytic differentiation, while depleting leukemia-associated monocytes in B-ALL animal models prolongs disease remission in vivo. Our profiling of the B-ALL immune microenvironment identifies extrinsic regulators of B-ALL survival supporting new immune-based therapeutic approaches for high-risk B-ALL treatment.
- Published
- 2020
23. What syndrome is this? Nail-patella syndrome
- Author
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Deidre, Buddin, Cynthia, Loomis, Tor, Shwayder, and Mary Wu, Chang
- Subjects
Radiography ,Nail-Patella Syndrome ,Humans ,Female ,Child - Published
- 2002
24. The cholinergic system of the primitive streak chick embryo
- Author
-
Cynthia Loomis and Jay E. Valinsky
- Subjects
Primitive streak ,Embryogenesis ,Embryo ,Biological Transport ,Chick Embryo ,Gastrula ,Biology ,Acetylcholinesterase ,Acetylcholine ,Cell biology ,Choline ,Choline O-Acetyltransferase ,Gastrulation ,Molecular Weight ,chemistry.chemical_compound ,Neurulation ,chemistry ,Biochemistry ,medicine ,Animals ,Choline transport ,Developmental Biology ,medicine.drug - Abstract
The presence of neurotransmitters at stages of embryonic development prior to neurulation has been demonstrated in several systems. Although the functions of these molecules at early stages of embryogenesis have not been ascertained, it is possible that they are involved in aspects of cell migration, regulation of the synthesis of macromolecules, intercellular communication, and in the transmission of positional information during gastrulation. As an initial approach to the resolution of questions concerning the function of transmitters during early development, we have begun a study of the cholinergic system in the primitive streak chick embryo (Hamburger-Hamilton stages 3 + to 5). We have found that the chick embryo: (1) can use exogenously applied choline for the synthesis of acetylcholine; (2) possesses a true acetylcholinesterase, which is predominantly in the form of the 4-6s monomer; and (3) can take up exogenous choline through a sodium-dependent, high-affinity choline transport system. To date we do not have any evidence for the presence of nicotinic or muscarinic receptors at the primitive streak stage.
- Published
- 1984
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