35 results on '"Micevic, Goran"'
Search Results
2. Clinical and Histologic Variants of CD8+ Cutaneous T-Cell Lymphomas.
- Author
-
Swallow, Madisen A., Micevic, Goran, Zhou, Amanda, Carlson, Kacie R., Foss, Francine M., and Girardi, Michael
- Subjects
- *
T cells , *MYCOSIS fungoides , *CUTANEOUS T-cell lymphoma , *IMMUNOHISTOCHEMISTRY , *HISTOLOGICAL techniques , *LYMPHOPROLIFERATIVE disorders , *CELL differentiation , *STAINS & staining (Microscopy) , *PHENOTYPES - Abstract
Simple Summary: CD8+ CTCL subtypes manifest with widespread clinical, histologic, and phenotypic features that inform the classification of the disease. Through this review, we highlight the importance of utilizing the synergy of clinical, histologic, and immunohistochemical findings to determine a correct diagnosis and applicable treatment plan. Although the vast majority of CTCL subtypes are of the CD4+ T-helper cell differentiation phenotype, there is a spectrum of CD8+ variants that manifest wide-ranging clinical, histologic, and phenotypic features that inform the classification of the disease. CD8, like CD4, and cytotoxic molecules (including TIA and granzyme) are readily detectable via IHC staining of tissue and, when expressed on the phenotypically abnormal T-cell population, can help distinguish specific CTCL subtypes. Nonetheless, given that the histopathologic differential for CD8+ lymphoproliferative disorders and lymphomas may range from very indolent lymphomatoid papulosis (LyP) to aggressive entities like CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (AECTCL), CD8 and/or cytotoxic molecule expression alone is insufficient for diagnosis and is not in itself an indicator of prognosis. We present a review of CTCL subtypes that can demonstrate CD8 positivity: CD8+ mycosis fungoides (MF), LyP type D, subcutaneous panniculitis-like T-cell lymphoma (SPTCL), primary cutaneous gamma/delta T-cell lymphoma (PCGDTL), CD8+ AECTCL, and acral CD8+ T-cell lymphoproliferative disorder (acral CD8+ TCLPD). These diseases may have different clinical manifestations and distinctive treatment algorithms. Due to the rare nature of these diseases, it is imperative to integrate clinical, histologic, and immunohistochemical findings to determine an accurate diagnosis and an appropriate treatment plan. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
3. KDM5B promotes immune evasion by recruiting SETDB1 to silence retroelements
- Author
-
Zhang, Shang-Min, Cai, Wesley L., Liu, Xiaoni, Thakral, Durga, Luo, Jiesi, Chan, Lok Hei, McGeary, Meaghan K., Song, Eric, Blenman, Kim R., Micevic, Goran, Jessel, Shlomit, Zhang, Yangyi, Yin, Mingzhu, Booth, Carmen J., Jilaveanu, Lucia B., Damsky, William, and Sznol, Mario
- Subjects
Tumors -- Care and treatment ,Immunotherapy -- Methods ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Tumours use various strategies to evade immune surveillance.sup.1,2. Immunotherapies targeting tumour immune evasion such as immune checkpoint blockade have shown considerable efficacy on multiple cancers.sup.3,4 but are ineffective for most patients due to primary or acquired resistance.sup.5-7. Recent studies showed that some epigenetic regulators suppress anti-tumour immunity.sup.2,8-12, suggesting that epigenetic therapies could boost anti-tumour immune responses and overcome resistance to current immunotherapies. Here we show that, in mouse melanoma models, depletion of KDM5B--an H3K4 demethylase that is critical for melanoma maintenance and drug resistance.sup.13-15--induces robust adaptive immune responses and enhances responses to immune checkpoint blockade. Mechanistically, KDM5B recruits the H3K9 methyltransferase SETDB1 to repress endogenous retroelements such as MMVL30 in a demethylase-independent manner. Derepression of these retroelements activates cytosolic RNA-sensing and DNA-sensing pathways and the subsequent type-I interferon response, leading to tumour rejection and induction of immune memory. Our results demonstrate that KDM5B suppresses anti-tumour immunity by epigenetic silencing of retroelements. We therefore reveal roles of KDM5B in heterochromatin regulation and immune evasion in melanoma, opening new paths for the development of KDM5B-targeting and SETDB1-targeting therapies to enhance tumour immunogenicity and overcome immunotherapy resistance. KDM5B recruits SETDB1 to repress endogenous retroelements such as MMVL30, suppressing anti-tumour immunity, and the depletion of KDM5B induces a robust adaptive immune response and enhances the response to immune checkpoint blockade., Author(s): Shang-Min Zhang [sup.1] , Wesley L. Cai [sup.1] [sup.12] , Xiaoni Liu [sup.1] [sup.2] , Durga Thakral [sup.2] , Jiesi Luo [sup.3] [sup.4] , Lok Hei Chan [sup.1] , [...]
- Published
- 2021
- Full Text
- View/download PDF
4. RAP80 and BRCA1 PARsylation protect chromosome integrity by preventing retention of BRCA1-B/C complexes in DNA repair foci
- Author
-
Vohhodina, Jekaterina, Toomire, Kimberly J., Petit, Sarah A., Micevic, Goran, Kumari, Geeta, Botchkarev, Vladimir V., Li, Zhe, Livingston, David M., and Hu, Yiduo
- Published
- 2020
5. Melanoma tumour-infiltrating T-lymphocyte therapy heralds the era of cell-based immunotherapies for solid tumours.
- Author
-
Talty, Ronan, Richmond, Rhys, and Micevic, Goran
- Subjects
MELANOMA ,REGULATORY T cells ,TUMORS ,CHIMERIC antigen receptors - Abstract
The article discusses the recent approval of a cell therapy called lifileucel for the treatment of melanoma. Lifileucel uses a patient's own tumor-infiltrating T lymphocytes (TILs) to target and treat melanoma. This approval marks a significant advancement in cancer treatment, as it is the first cell therapy to be approved for a solid tumor. Clinical trials have shown that lifileucel has a response rate between 30% and 50%, making it a valuable addition to the treatment options for melanoma patients who do not respond to other therapies. However, there are still challenges to overcome, such as the need for a surgical procedure to isolate TILs and the exclusion of patients with certain conditions. Ongoing research is focused on improving the effectiveness and specificity of T-cell therapies for melanoma. [Extracted from the article]
- Published
- 2024
- Full Text
- View/download PDF
6. p90RSK Blockade Inhibits Dual BRAF and MEK Inhibitor-Resistant Melanoma by Targeting Protein Synthesis
- Author
-
Theodosakis, Nicholas, Micevic, Goran, Langdon, Casey G., Ventura, Alessandra, Means, Robert, Stern, David F., and Bosenberg, Marcus W.
- Published
- 2017
- Full Text
- View/download PDF
7. Cutaneous diatoms from diatomaceous earth mimicking myiasis infection
- Author
-
Roy, Simon F., Micevic, Goran, McNiff, Jennifer M., Christensen, Sean R., and Cowper, Shawn E.
- Published
- 2024
- Full Text
- View/download PDF
8. IL-7R licenses a population of epigenetically poised memory CD8+ T cells with superior antitumor efficacy that are critical for melanoma memory.
- Author
-
Micevic, Goran, Daniels, Andrew, Flem-Karlsen, Karine, Park, Koonam, Talty, Ronan, McGeary, Meaghan, Mirza, Haris, Blackburn, Holly N., Sefik, Esen, Cheung, Julie F., Hornick, Noah I., Aizenbud, Lilach, Joshi, Nikhil S., Kluger, Harriet, Iwasaki, Akiko, Bosenberg, Marcus W., and Flavell, Richard A.
- Subjects
- *
IMMUNOLOGIC memory , *MELANOMA , *T cells , *PROGNOSIS , *DNA methylation - Abstract
Recurrence of advanced melanoma after therapy is a major risk factor for reduced survival, and treatment options are limited. Antitumor immune memory plays a critical role in preventing melanoma recurrence and memory T cells could be a potent cell-based therapy, but the identity, and functional properties of the required immune cells are incompletely understood. Here, we show that an IL-7Rhi tumor-specific CD8+ population is critical for antitumor memory and can be epigenetically augmented to drive powerful antitumor immune responses. Using a model of functional antimelanoma memory, we found that high IL-7R expression selectively marks a CD8+ population in lymphoid organs that plays critical roles in maintaining tumor remission after immunotherapy or surgical resection. This population has intrinsic cytotoxic activity, lacks markers of exhaustion and has superior antitumor efficacy. IL-7Rhi cells have a functionally poised epigenetic landscape regulated by DNA methylation, which can be augmented by hypomethylating agents to confer improved survival and complete melanoma clearance in naive mice. Importantly, greater than 95% of tumor-specific T cells in draining lymph nodes after therapy express high levels of IL-7R. This overlap between IL-7Rhi and antigen-specific T cells allows for enrichment of a potent functional CD8+ population without determining antigen-specificity, which we demonstrate in a melanoma model without a known antigen. We identify that IL-7R expression in human melanoma is an independent prognostic factor of improved survival. These findings advance our basic understanding of antitumor memory and suggest a cell-based therapy using high IL-7R expression to enrich for a lymph node population with superior antitumor activity that can be augmented by hypomethylating agents. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
9. New insights into programmed cell death protein 1 blockade-associated cutaneous immune-related adverse events.
- Author
-
Micevic, Goran, Daniels, Andrew, and Flavell, Richard A
- Subjects
- *
DRUG side effects , *ALOPECIA areata , *REGULATORY T cells , *SKIN cancer , *PROGRAMMED cell death 1 receptors - Abstract
Multiple ligand-receptor interactions between antigen-specific T cells and macrophages in the dermis could help explain how PD-1 controls the location of self-antigen-specific T cells and compartmentalizes T cells away from self-antigens. For example, anti-PD-1 antibody leads to activation of CD8 SP + sp T cells recognizing hair follicle autoantigens on keratinocytes in checkpoint-associa--ted alopecia areata.[13] However, the origin of these autoantigen recognizing T cells and whether they derive from previously tolerant T cells or arise I de novo i is unclear. (Right) PD-1 blockade leads to loss of T-cell tolerance to self-antigen, localization of self-antigen-specific T cells to the epidermis, increased cytokine release, keratinocyte death and skin inflammation. [Extracted from the article]
- Published
- 2023
- Full Text
- View/download PDF
10. Stereotactic Ablative Radiation Therapy Combined With Immunotherapy for Solid Tumors
- Author
-
Brooks, Eric D., Schoenhals, Jonathan E., Tang, Chad, Micevic, Goran, Gomez, Daniel R., Chang, Joe Y., and Welsh, James W.
- Published
- 2016
- Full Text
- View/download PDF
11. Integrative discovery of CD98 as a melanoma biomarker
- Author
-
Theodosakis, Nicholas, Micevic, Goran, Sharma, Reema, Baras, Alexander S., Lazova, Rossitza, Bosenberg, Marcus W., and Rodić, Nemanja
- Published
- 2016
- Full Text
- View/download PDF
12. Leukoderma Induced by Rotigotine Patch, a Transdermal Dopamine Agonist.
- Author
-
Talty, Ronan, Micevic, Goran, Wang, Alice, Ko, Christine J., and Damsky, William
- Subjects
- *
DOPAMINE agonists , *VITILIGO , *RESTLESS legs syndrome , *TRANSDERMAL medication , *HYPOPIGMENTATION - Abstract
Leukoderma, or hypomelanosis of the skin, can occur in response to various chemical and pharmacologic substances ranging from topical medications to optic preparations and systemic medications. In this case report, we present a 78-year-old man with a history of restless leg syndrome (RLS) who had been using rotigotine transdermal patches once daily for 1 year and developed leukoderma on the bilateral anterior shoulders in the area of patch application. Histopathologic examination showed an absence of melanocytes at the dermal-epidermal junction confirmed by Melan A stain. While the patient was not bothered by the depigmentation and elected to continue the rotigotine patch for his RLS, this case highlights leukoderma as a potential side effect of dopamine transdermal patches and offers insight into the potential mechanism of hypopigmentation in response to dopamine agonism. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
13. Erythrodermic scabies in an immunocompetent patient
- Author
-
Talty, Ronan, Micevic, Goran, Damsky, William, and King, Brett A.
- Published
- 2022
- Full Text
- View/download PDF
14. Perniolike lesions and coagulopathy in a patient with COVID-19 infection
- Author
-
Micevic, Goran, Morris, Jensa, Lee, Alfred Ian, and King, Brett A.
- Published
- 2020
- Full Text
- View/download PDF
15. PD‐L1 methylation regulates PD‐L1 expression and is associated with melanoma survival.
- Author
-
Micevic, Goran, Thakral, Durga, McGeary, Meaghan, and Bosenberg, Marcus W.
- Subjects
- *
DNA methylation , *MELANOMA , *GENE expression , *INTERFERONS , *EPIGENETICS - Abstract
The aim of this study is to determine the significance of programmed death ligand 1 (PD‐L1 or CD274) methylation in relation to PD‐L1 expression and survival in melanoma. Despite the clinical importance of therapies targeting the PD‐1/PD‐L1 immune checkpoint in melanoma, factors regulating PD‐L1 expression, including epigenetic mechanisms, are not completely understood. In this study, we examined PD‐L1 promoter methylation in relation to PD‐L1 expression and overall survival in melanoma patients. Our results suggest that DNA methylation regulates PD‐L1 expression in melanoma, and we identify the key methylated CpG loci in the PD‐L1 promoter, establish PD‐L1 methylation as an independent survival prognostic factor, provide proof of concept for altering PD‐L1 expression by hypomethylating agents, and uncover that PD‐L1 methylation is associated with an interferon signaling transcriptional phenotype. Based on our findings, measuring and altering PD‐L1 promoter DNA methylation may have potential prognostic and therapeutic applications in melanoma. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
16. Inhibition of isoprenylation synergizes with MAPK blockade to prevent growth in treatment‐resistant melanoma, colorectal, and lung cancer.
- Author
-
Theodosakis, Nicholas, Langdon, Casey G., Micevic, Goran, Krykbaeva, Irina, Means, Robert E., Stern, David F., and Bosenberg, Marcus W.
- Subjects
MELANOMA treatment ,COLON cancer ,LUNG cancer ,ISOPRENYLATION ,ISOPENTENOIDS - Abstract
This study evaluates the use of HMG‐CoA reductase inhibitors, or statins, as an adjunctive to BRAF and MEK inhibition as a treatment in melanomas and other tumors with driver mutations in the MAPK pathway. Experiments used simvastatin in conjunction with vemurafenib and selumetinib in vitro and simvastatin with vemurafenib in vivo to demonstrate additional growth abrogation beyond MAPK blockade alone. Additional studies demonstrated that statin anti‐tumor effects appeared to depend on inhibition of isoprenoid synthesis given rescue with add‐back of downstream metabolites. Ultimately, we concluded that statins represent a possible useful adjunctive therapy in MAPK‐driven tumors when given with current approved targeted therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
17. Balanitis associated with FOLFIRI chemotherapy
- Author
-
Micevic, Goran, Perkins, Sara Harcharik, and Zubek, Amanda E.
- Published
- 2018
- Full Text
- View/download PDF
18. (S029) Development of an Immune-Associated Molecular Signature Predicting Melanoma Survival
- Author
-
Micevic, Goran, Muthusamy, Viswanathan, Pupo, Gulietta, Scolyer, Richard, Long, Georgina, and Bosenberg, Marcus
- Published
- 2017
- Full Text
- View/download PDF
19. UV-induced somatic mutations elicit a functional T cell response in the YUMMER1.7 mouse melanoma model.
- Author
-
Wang, Jake, Perry, Curtis J., Meeth, Katrina, Thakral, Durga, Damsky, William, Micevic, Goran, Kaech, Susan, Blenman, Kim, and Bosenberg, Marcus
- Subjects
MELANOMA ,SKIN cancer ,NEUROENDOCRINE tumors ,DYSPLASTIC nevus syndrome ,CHIMERIC antigen receptors - Abstract
Human melanomas exhibit relatively high somatic mutation burden compared to other malignancies. These somatic mutations may produce neoantigens that are recognized by the immune system, leading to an antitumor response. By irradiating a parental mouse melanoma cell line carrying three driver mutations with UVB and expanding a single-cell clone, we generated a mutagenized model that exhibits high somatic mutation burden. When inoculated at low cell numbers in immunocompetent C57 BL/6J mice, YUMMER1.7 (Yale University Mouse Melanoma Exposed to Radiation) regresses after a brief period of growth. This regression phenotype is dependent on T cells as YUMMER1.7 tumors grow significantly faster in immunodeficient Rag1
−/− mice and C57 BL/6J mice depleted of CD4 and CD8 T cells. Interestingly, regression can be overcome by injecting higher cell numbers of YUMMER1.7, which results in tumors that grow without effective rejection. Mice that have previously rejected YUMMER1.7 tumors develop immunity against higher doses of YUMMER1.7 tumor challenge. In addition, escaping YUMMER1.7 tumors are sensitive to anti- CTLA-4 and anti- PD-1 therapy, establishing a new model for the evaluation of immune checkpoint inhibition and antitumor immune responses. [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
- View/download PDF
20. Aberrant DNA methylation in melanoma: biomarker and therapeutic opportunities.
- Author
-
Micevic, Goran, Theodosakis, Nicholas, and Bosenberg, Marcus
- Subjects
- *
DNA methylation , *MELANOMA , *BIOMARKERS - Abstract
Aberrant DNA methylation is an epigenetic hallmark of melanoma, known to play important roles in melanoma formation and progression. Recent advances in genome-wide methylation methods have provided the means to identify differentially methylated genes, methylation signatures, and potential biomarkers. However, despite considerable effort and advances in cataloging methylation changes in melanoma, many questions remain unanswered. The aim of this review is to summarize recent developments, emerging trends, and important unresolved questions in the field of aberrant DNA methylation in melanoma. In addition to reviewing recent developments, we carefully synthesize the findings in an effort to provide a framework for understanding the current state and direction of the field. To facilitate clarity, we divided the review into DNA methylation changes in melanoma, biomarker opportunities, and therapeutic developments. We hope this review contributes to accelerating the utilization of the diagnostic, prognostic, and therapeutic potential of DNA methylation for the benefit of melanoma patients. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
21. Attenuation of genome-wide 5-methylcytosine level is an epigenetic feature of cutaneous malignant melanomas.
- Author
-
Micevic, Goran, Theodosakis, Nicholas, Taube, Janis M., Bosenberg, Marcus W., and Rodić, Nemanja
- Published
- 2017
- Full Text
- View/download PDF
22. The YUMM lines: a series of congenic mouse melanoma cell lines with defined genetic alterations.
- Author
-
Meeth, Katrina, Wang, Jake Xiao, Micevic, Goran, Damsky, William, and Bosenberg, Marcus W.
- Subjects
CELLULAR therapy ,CELLS ,CANCER cells ,CELL lines ,IMMUNOCOMPETENT cells ,MICE ,ANIMAL experimentation ,CANCER - Abstract
The remarkable success of immune therapies emphasizes the need for immune-competent cancer models. Elegant genetically engineered mouse models of a variety of cancers have been established, but their effective use is limited by cost and difficulties in rapidly generating experimental data. Some mouse cancer cell lines are transplantable to immunocompetent host mice and have been utilized extensively to study cancer immunology. Here, we describe the Yale University Mouse Melanoma (YUMM) lines, a comprehensive system of mouse melanoma cell lines that are syngeneic to C57 BL/6, have well-defined human-relevant driver mutations, and are genomically stable. This will be a useful tool for the study of tumor immunology and genotype-specific cancer biology. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
23. Cell and Tissue Display: An Alternative Multipurpose Tool for Microscopy.
- Author
-
Theodosakis, Nicholas, Micevic, Goran, Bosenberg, Marcus W., and Rodić, Nemanja
- Subjects
MICROSCOPY ,CELL lines ,AGAROSE ,BIOPSY ,LABORATORIES - Abstract
We developed a method, termed Cell and Tissue Display (CTD), for embedding 16 or more different tissue samples in multi-compartment agarose blocks. The CTD-generated blocks allow uniform multiplexing of cell lines and small tissue fragments within a single histologic block. The distribution of individual cells within the CTD blocks is improved, likely because the individual agarose compartments are small and uniform. The composition of each CTD block can be customized based on intended use. Some potential uses of CTD histologic blocks include improved sectioning of small tissue fragments, such as needle biopsy specimens or punch biopsies; multiplexing of tissue fragments within a single block; and the generation of control slides for laboratory proficiency testing. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
24. Genome-wide characterization of human L1 antisense promoter-driven transcripts.
- Author
-
Criscione, Steven W., Theodosakis, Nicholas, Micevic, Goran, Cornish, Toby C., Burns, Kathleen H., Neretti, Nicola, and Rodić, Nemanja
- Subjects
HUMAN genome ,GENETIC transcription ,TRANSCRIPTION factors ,PROMOTERS (Genetics) ,RNA sequencing - Abstract
Background: Long INterspersed Element-1 (LINE-1 or L1) is the only autonomously active, transposable element in the human genome. L1 sequences comprise approximately 17 % of the human genome, but only the evolutionarily recent, human-specific subfamily is retrotransposition competent. The L1 promoter has a bidirectional orientation containing a sense promoter that drives the transcription of two proteins required for retrotransposition and an antisense promoter. The L1 antisense promoter can drive transcription of chimeric transcripts: 5' L1 antisense sequences spliced to the exons of neighboring genes. Results: The impact of L1 antisense promoter activity on cellular transcriptomes is poorly understood. To investigate this, we analyzed GenBank ESTs for messenger RNAs that initiate in the L1 antisense promoter. We identified 988 putative L1 antisense chimeric transcripts, 911 of which have not been previously reported. These appear to be alternative genic transcripts, sense-oriented with respect to gene and initiating near, but typically downstream of, the gene transcriptional start site. In multiple cell lines, L1 antisense promoters display enrichment for YY1 transcription factor and histone modifications associated with active promoters. Global run-on sequencing data support the activity of the L1 antisense promoter. We independently detected 124 L1 antisense chimeric transcripts using long read Pacific Biosciences RNA-seq data. Furthermore, we validated four chimeric transcripts by quantitative RT-PCR and Sanger sequencing and demonstrated that they are readily detectable in many normal human tissues. Conclusions: We present a comprehensive characterization of human L1 antisense promoter-driven transcripts and provide substantial evidence that they are transcribed in a variety of human cell-types. Our findings reveal a new wide-reaching aspect of L1 biology by identifying antisense transcripts affecting as many as 4 % of all human genes. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
25. Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma.
- Author
-
Chen, Fengju, Zhang, Yiqun, Şenbabaoğlu, Yasin, Ciriello, Giovanni, Yang, Lixing, Reznik, Ed, Shuch, Brian, Micevic, Goran, De Velasco, Guillermo, Shinbrot, Eve, Noble, Michael S., Lu, Yiling, Covington, Kyle R., Xi, Liu, Drummond, Jennifer A., Muzny, Donna, Kang, Hyojin, Lee, Junehawk, Tamboli, Pheroze, and Reuter, Victor
- Abstract
Summary On the basis of multidimensional and comprehensive molecular characterization (including DNA methalylation and copy number, RNA, and protein expression), we classified 894 renal cell carcinomas (RCCs) of various histologic types into nine major genomic subtypes. Site of origin within the nephron was one major determinant in the classification, reflecting differences among clear cell, chromophobe, and papillary RCC. Widespread molecular changes associated with TFE3 gene fusion or chromatin modifier genes were present within a specific subtype and spanned multiple subtypes. Differences in patient survival and in alteration of specific pathways (including hypoxia, metabolism, MAP kinase, NRF2-ARE, Hippo, immune checkpoint, and PI3K/AKT/mTOR) could further distinguish the subtypes. Immune checkpoint markers and molecular signatures of T cell infiltrates were both highest in the subtype associated with aggressive clear cell RCC. Differences between the genomic subtypes suggest that therapeutic strategies could be tailored to each RCC disease subset. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
26. DNMT3b Modulates Melanoma Growth by Controlling Levels of mTORC2 Component RICTOR.
- Author
-
Micevic, Goran, Muthusamy, Viswanathan, Damsky, William, Theodosakis, Nicholas, Liu, Xiaoni, Meeth, Katrina, Wingrove, Emily, Santhanakrishnan, Manjula, and Bosenberg, Marcus
- Abstract
Summary DNA methyltransferase DNMT3B is frequently overexpressed in tumor cells and plays important roles during the formation and progression of several cancer types. However, the specific signaling pathways controlled by DNMT3B in cancers, including melanoma, are poorly understood. Here, we report that DNMT3B plays a pro-tumorigenic role in human melanoma and that DNMT3B loss dramatically suppresses melanoma formation in the Braf / Pten mouse melanoma model. Loss of DNMT3B results in hypomethylation of the miR-196b promoter and increased miR-196b expression, which directly targets the mTORC2 component Rictor. Loss of RICTOR in turn prevents mTORC2 activation, which is critical for melanoma formation and growth. These findings establish Dnmt3b as a regulator of melanoma formation through its effect on mTORC2 signaling. Based on these results, DNMT3B is a potential therapeutic target in melanoma. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
27. mTORC1 Activation Blocks BrafV600E-Induced Growth Arrest but Is Insufficient for Melanoma Formation.
- Author
-
Damsky, William, Micevic, Goran, Meeth, Katrina, Muthusamy, Viswanathan, Curley, David P., Santhanakrishnan, Manjula, Erdelyi, Ildiko, Platt, James T., Huang, Laura, Theodosakis, Nicholas, Zaidi, M. Raza, Tighe, Scott, Davies, Michael A., Dankort, David, McMahon, Martin, Merlino, Glenn, Bardeesy, Nabeel, and Bosenberg, Marcus
- Subjects
- *
CANCER invasiveness , *CANCER cells , *MTOR protein , *CELLULAR signal transduction , *TUMOR growth , *LABORATORY mice - Abstract
Summary Braf V600E induces benign, growth-arrested melanocytic nevus development, but also drives melanoma formation. Cdkn2a loss in Braf V600E melanocytes in mice results in rare progression to melanoma, but only after stable growth arrest as nevi. Immediate progression to melanoma is prevented by upregulation of miR-99/100, which downregulates mTOR and IGF1R signaling. mTORC1 activation through Stk11 ( Lkb1 ) loss abrogates growth arrest of Braf V600E melanocytic nevi, but is insufficient for complete progression to melanoma. Cdkn2a loss is associated with mTORC2 and Akt activation in human and murine melanocytic neoplasms. Simultaneous Cdkn2a and Lkb1 inactivation in Braf V600E melanocytes results in activation of both mTORC1 and mTORC2/Akt, inducing rapid melanoma formation in mice. In this model, activation of both mTORC1/2 is required for Braf-induced melanomagenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
28. Mitochondrial function in melanoma.
- Author
-
Theodosakis, Nicholas, Micevic, Goran, Kelly, Daniel P., and Bosenberg, Marcus
- Subjects
- *
MELANOMA , *MITOCHONDRIA , *SKIN cancer , *APOPTOSIS , *CELL metabolism , *CLINICAL trials - Abstract
Melanoma is the most lethal form of skin cancer and its incidence is rapidly rising. Breakthroughs in the understanding of the basic biology of melanoma in the past decade have yielded several new treatments, and advances continue to be made on a variety of fronts. One such area involves the delineation of changes in mitochondria that occur during melanoma formation, and how these changes affect responses to therapy. In this review, we summarize recent developments on the multiple functions that mitochondria play in melanoma, and how these roles are currently being evaluated as new targets for clinical intervention. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
29. Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses.
- Author
-
Ho, Ping-Chih, Bihuniak, Jessica Dauz, Macintyre, Andrew N., Staron, Matthew, Liu, Xiaojing, Amezquita, Robert, Tsui, Yao-Chen, Cui, Guoliang, Micevic, Goran, Perales, Jose C., Kleinstein, Steven H., Abel, E. Dale, Insogna, Karl L., Feske, Stefan, Locasale, Jason W., Bosenberg, Marcus W., Rathmell, Jeffrey C., and Kaech, Susan M.
- Subjects
- *
PYRUVATE kinase , *ANTINEOPLASTIC agents , *T cells , *GLYCOLYSIS , *CANCER cell growth , *CANCER cell proliferation , *CANCER immunotherapy , *GENETIC overexpression - Abstract
Summary Activated T cells engage aerobic glycolysis and anabolic metabolism for growth, proliferation, and effector functions. We propose that a glucose-poor tumor microenvironment limits aerobic glycolysis in tumor-infiltrating T cells, which suppresses tumoricidal effector functions. We discovered a new role for the glycolytic metabolite phosphoenolpyruvate (PEP) in sustaining T cell receptor-mediated Ca 2+ -NFAT signaling and effector functions by repressing sarco/ER Ca 2+ -ATPase (SERCA) activity. Tumor-specific CD4 and CD8 T cells could be metabolically reprogrammed by increasing PEP production through overexpression of phosphoenolpyruvate carboxykinase 1 (PCK1), which bolstered effector functions. Moreover, PCK1-overexpressing T cells restricted tumor growth and prolonged the survival of melanoma-bearing mice. This study uncovers new metabolic checkpoints for T cell activity and demonstrates that metabolic reprogramming of tumor-reactive T cells can enhance anti-tumor T cell responses, illuminating new forms of immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
30. IL-7R licenses a population of epigenetically poised memory CD8 + T cells with superior antitumor efficacy that are critical for melanoma memory.
- Author
-
Micevic G, Daniels A, Flem-Karlsen K, Park K, Talty R, McGeary M, Mirza H, Blackburn HN, Sefik E, Cheung JF, Hornick NI, Aizenbud L, Joshi NS, Kluger H, Iwasaki A, Bosenberg MW, and Flavell RA
- Subjects
- Mice, Humans, Animals, Memory T Cells, Signal Transduction, Antigens, Licensure, Immunologic Memory, CD8-Positive T-Lymphocytes, Melanoma genetics, Melanoma therapy
- Abstract
Recurrence of advanced melanoma after therapy is a major risk factor for reduced survival, and treatment options are limited. Antitumor immune memory plays a critical role in preventing melanoma recurrence and memory T cells could be a potent cell-based therapy, but the identity, and functional properties of the required immune cells are incompletely understood. Here, we show that an IL-7R
hi tumor-specific CD8+ population is critical for antitumor memory and can be epigenetically augmented to drive powerful antitumor immune responses. Using a model of functional antimelanoma memory, we found that high IL-7R expression selectively marks a CD8+ population in lymphoid organs that plays critical roles in maintaining tumor remission after immunotherapy or surgical resection. This population has intrinsic cytotoxic activity, lacks markers of exhaustion and has superior antitumor efficacy. IL-7Rhi cells have a functionally poised epigenetic landscape regulated by DNA methylation, which can be augmented by hypomethylating agents to confer improved survival and complete melanoma clearance in naive mice. Importantly, greater than 95% of tumor-specific T cells in draining lymph nodes after therapy express high levels of IL-7R. This overlap between IL-7Rhi and antigen-specific T cells allows for enrichment of a potent functional CD8+ population without determining antigen-specificity, which we demonstrate in a melanoma model without a known antigen. We identify that IL-7R expression in human melanoma is an independent prognostic factor of improved survival. These findings advance our basic understanding of antitumor memory and suggest a cell-based therapy using high IL-7R expression to enrich for a lymph node population with superior antitumor activity that can be augmented by hypomethylating agents.- Published
- 2023
- Full Text
- View/download PDF
31. Setdb1 -loss induces type-I interferons and immune clearance of melanoma.
- Author
-
McGeary MK, Damsky W, Daniels A, Song E, Micevic G, Huet-Calderwood C, Lou HJ, Paradkar S, Kaech S, Calderwood DA, Turk BE, Iwasaki A, and Bosenberg MW
- Abstract
Despite recent advances in the treatment of melanoma, many patients with metastatic disease still succumb to their disease. To identify tumor-intrinsic modulators of immunity to melanoma, we performed a whole-genome CRISPR screen in melanoma and identified multiple components of the HUSH complex, including Setdb1 , as hits. We found that loss of Setdb1 leads to increased immunogenicity and complete tumor clearance in a CD8+ T-cell dependent manner. Mechanistically, loss of Setdb1 causes de-repression of endogenous retroviruses (ERVs) in melanoma cells and triggers tumor-cell intrinsic type-I interferon signaling, upregulation of MHC-I expression, and increased CD8+ T-cell infiltration. Furthermore, spontaneous immune clearance observed in Setdb1
-/- tumors results in subsequent protection from other ERV-expressing tumor lines, supporting the functional anti-tumor role of ERV-specific CD8+ T-cells found in the Setdb1-/- microenvironment. Blocking the type-I interferon receptor in mice grafted with Setdb1-/- tumors decreases immunogenicity by decreasing MHC-I expression, leading to decreased T-cell infiltration and increased melanoma growth comparable to Setdb1wt tumors. Together, these results indicate a critical role for Setdb1 and type-I interferons in generating an inflamed tumor microenvironment, and potentiating tumor-cell intrinsic immunogenicity in melanoma. This study further emphasizes regulators of ERV expression and type-I interferon expression as potential therapeutic targets for augmenting anti-cancer immune responses.- Published
- 2023
- Full Text
- View/download PDF
32. The Crossroads of Cancer Epigenetics and Immune Checkpoint Therapy.
- Author
-
Micevic G, Bosenberg MW, and Yan Q
- Subjects
- Humans, Epigenesis, Genetic, Immunotherapy, Pancreatic Neoplasms
- Abstract
Immune checkpoint inhibitors (ICI) have significantly improved treatment outcomes for several types of cancer over the past decade, but significant challenges that limit wider effectiveness of current immunotherapies remain to be addressed. Certain "cold" tumor types, such as pancreatic cancer, exhibit very low response rates to ICI due to intrinsically low immunogenicity. In addition, many patients who initially respond to ICI lack a sustained response due to T-cell exhaustion. Several recent studies show that epigenetic modifiers, such as SETDB1 and LSD1, can play critical roles in regulating both tumor cell-intrinsic immunity and T-cell exhaustion. Here, we review the evidence showing that multiple epigenetic regulators silence the expression of endogenous antigens, and their loss induces viral mimicry responses bolstering the response of "cold" tumors to ICI in preclinical models. Similarly, a previously unappreciated role for epigenetic enzymes is emerging in the establishment and maintenance of stem-like T-cell populations that are critical mediators of response to ICI. Targeting the crossroads of epigenetics and immune checkpoint therapy has tremendous potential to improve antitumor immune responses and herald the next generation of sustained responses in immuno-oncology., (©2022 American Association for Cancer Research.)
- Published
- 2023
- Full Text
- View/download PDF
33. Structure-Guided Identification of DNMT3B Inhibitors.
- Author
-
Newton AS, Faver JC, Micevic G, Muthusamy V, Kudalkar SN, Bertoletti N, Anderson KS, Bosenberg MW, and Jorgensen WL
- Abstract
Methyltransferase 3 beta (DNMT3B) inhibitors that interfere with cancer growth are emerging possibilities for treatment of melanoma. Herein we identify small molecule inhibitors of DNMT3B starting from a homology model based on a DNMT3A crystal structure. Virtual screening by docking led to purchase of 15 compounds, among which 5 were found to inhibit the activity of DNMT3B with IC
50 values of 13-72 μM in a fluorogenic assay. Eight analogues of 7 , 10 , and 12 were purchased to provide 2 more active compounds. Compound 11 is particularly notable as it shows good selectivity with no inhibition of DNMT1 and 22 μM potency toward DNMT3B. Following additional de novo design, exploratory synthesis of 17 analogues of 11 delivered 5 additional inhibitors of DNMT3B with the most potent being 33h with an IC50 of 8.0 μM. This result was well confirmed in an ultrahigh-performance liquid chromatography (UHPLC)-based analytical assay, which yielded an IC50 of 4.8 μM. Structure-activity data are rationalized based on computed structures for DNMT3B complexes., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)- Published
- 2020
- Full Text
- View/download PDF
34. Balanitis associated with FOLFIRI chemotherapy.
- Author
-
Micevic G, Perkins SH, and Zubek AE
- Published
- 2017
- Full Text
- View/download PDF
35. BRAF Inhibition Decreases Cellular Glucose Uptake in Melanoma in Association with Reduction in Cell Volume.
- Author
-
Theodosakis N, Held MA, Marzuka-Alcala A, Meeth KM, Micevic G, Long GV, Scolyer RA, Stern DF, and Bosenberg MW
- Subjects
- Biological Transport drug effects, Drug Resistance, Neoplasm, Flow Cytometry, Fluorodeoxyglucose F18 metabolism, Fluorodeoxyglucose F18 pharmacokinetics, Glucose pharmacokinetics, Hexokinase genetics, Hexokinase metabolism, Humans, Immunoblotting, Indoles pharmacology, Melanoma genetics, Melanoma pathology, Positron-Emission Tomography, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Proto-Oncogene Proteins B-raf genetics, RNA Interference, Sulfonamides pharmacology, Vemurafenib, Cell Size, Glucose metabolism, Melanoma metabolism, Proto-Oncogene Proteins B-raf metabolism
- Abstract
BRAF kinase inhibitors have dramatically affected treatment of BRAF(V600E) (/) (K)-driven metastatic melanoma. Early responses assessed using [(18)F]fluorodeoxyglucose uptake-positron emission tomography (FDG-PET) have shown dramatic reduction of radiotracer signal within 2 weeks of treatment. Despite high response rates, relapse occurs in nearly all cases, frequently at sites of treated metastatic disease. It remains unclear whether initial loss of (18)FDG uptake is due to tumor cell death or other reasons. Here, we provide evidence of melanoma cell volume reduction in a patient cohort treated with BRAF inhibitors. We present data demonstrating that BRAF inhibition reduces melanoma glucose uptake per cell, but that this change is no longer significant following normalization for cell volume changes. We also demonstrate that volume normalization greatly reduces differences in transmembrane glucose transport and hexokinase-mediated phosphorylation. Mechanistic studies suggest that this loss of cell volume is due in large part to decreases in new protein translation as a consequence of vemurafenib treatment. Ultimately, our findings suggest that cell volume regulation constitutes an important physiologic parameter that may significantly contribute to radiographic changes observed in clinic., (©2015 American Association for Cancer Research.)
- Published
- 2015
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.