Research & Publications
Extensive Research Description
Melanoma is the deadliest form of skin cancer with an enormous toll on human life and health. It is estimated that nearly 10,000 deaths and 74,000 new cases of melanoma occurred in the United States alone in 2015, while 132,000 new melanoma cases were reported worldwide. Despite advancements in therapy, metastatic melanoma is an aggressive disease with a poor 5-year overall survival rate of approximately 17%.
1) Epigenetic changes in melanoma
Genetic changes in melanoma have been largely well described over the past decade, but epigenetic changes and their functional roles in melanoma formation remain, comparatively, poorly understood. DNA methylation is an epigenetic change that is almost universally abnormal in melanoma. However, the specific role of individual DNMT enzymes (DNMT1, DNMT3A and DNMT3B), their methylation targets in melanoma, and signaling pathways affected are largely elusive. We used a mouse model of melanoma based on the most common human mutation, BrafV600E, in the context of Pten tumor suppressor loss to investigate the role, signaling changes and targets of DNA methyltransferases during melanoma formation and progression. By inactivating individual DNA methyltransferases, functional requirements for DNMT enzymes during melanoma formation and progression were delineated, suggesting that DNMT3B is the crucial methyltransferase during melanoma formation, and may be a target for melanoma therapy. Dnmt3b is overexpressed in human melanoma, associated with shorter 5-year overall survival, and allows for long term activation of mTORC2 by silencing repressive miRNAs. Dnmt3b methylates genes marked by the histone modification H3K27me3, is an important regulator of global methylation in melanoma, and targets many genes well recognized to be aberrantly methylated in melanoma.
2) Prognostic factors of melanoma survival
Apart from mechanistic insights and potential therapeutic targets, we study methylation based gene signatures that can predict patient survival, and may be a valuable biomarker. In addition to focal hypermethylation, we studied the role of aberrant global hypomethylation in melanoma and found that it may be required for melanoma cell survival, as induction of hypermethylation leads to cell death.
3) Understanding epigenetic regulation immune response to melanoma
Currently, the most promising therapy for melanoma, and certain other cancers such as NSCLC, is antibody mediated inhibition of immune checkpoint pathways (Valpione and Campana, 2016). Epigenetic changes have been long recognized to regulate expression of antigen presentation genes, such as MHC Class I genes, tumor antigens. such as MAGE and NY-ESO1, and, more recently, viral response and interferon pathway activation (Licht, 2015).. Perturbing DNA methylation and other epigenetic modifications may provide a pathway to augmenting anti tumor immune responses. Others have shown that methylation regulates expression of PD-1, PD-L1, PD-L2 and CTLA-4 in MDS (Yang et al., 2014a). We recently found that PD-L1 methylation in melanoma is associated with patient survival (Micevic et al. 2019), and can be targeted using hypomethylating agents. Understanding the epigenetic changes contributing to T-cell exhaustion in melanoma -- and how to control them -- would significantly advance our understanding of response to current therapies.
Collectively, our studies are focused on the role of genetic and epigenetic changes in melanoma development and growth, including uncovering novel targets, developing prognostic tools and therapeutic strategies for the benefit of melanoma patients.
- Targeting the neonatal Fc receptor in pemphigus: safety firstMicevic G, Lo SN, Rajan N. Targeting the neonatal Fc receptor in pemphigus: safety first British Journal Of Dermatology 2021, 186: 389-390. PMID: 34961930, PMCID: PMC9295899, DOI: 10.1111/bjd.20939.
- KDM5B promotes immune evasion by recruiting SETDB1 to silence retroelementsZhang SM, Cai WL, Liu X, Thakral D, Luo J, Chan LH, McGeary MK, Song E, Blenman KRM, Micevic G, Jessel S, Zhang Y, Yin M, Booth CJ, Jilaveanu LB, Damsky W, Sznol M, Kluger HM, Iwasaki A, Bosenberg MW, Yan Q. KDM5B promotes immune evasion by recruiting SETDB1 to silence retroelements Nature 2021, 598: 682-687. PMID: 34671158, PMCID: PMC8555464, DOI: 10.1038/s41586-021-03994-2.
- Perniolike lesions and coagulopathy in a patient with COVID-19 infectionMicevic G, Morris J, Lee AI, King BA. Perniolike lesions and coagulopathy in a patient with COVID-19 infection JAAD Case Reports 2020, 6: 1294-1296. PMID: 32953959, PMCID: PMC7491482, DOI: 10.1016/j.jdcr.2020.08.042.
- PD‐L1 methylation regulates PD‐L1 expression and is associated with melanoma survivalMicevic G, Thakral D, McGeary M, Bosenberg M. PD‐L1 methylation regulates PD‐L1 expression and is associated with melanoma survival Pigment Cell & Melanoma Research 2018, 32: 435-440. PMID: 30343532, PMCID: PMC6475614, DOI: 10.1111/pcmr.12745.
- UV‐induced somatic mutations elicit a functional T cell response in the YUMMER1.7 mouse melanoma modelWang J, Perry CJ, Meeth K, Thakral D, Damsky W, Micevic G, Kaech S, Blenman K, Bosenberg M. UV‐induced somatic mutations elicit a functional T cell response in the YUMMER1.7 mouse melanoma model Pigment Cell & Melanoma Research 2017, 30: 428-435. PMID: 28379630, PMCID: PMC5820096, DOI: 10.1111/pcmr.12591.
- p90RSK Blockade Inhibits Dual BRAF and MEK Inhibitor-Resistant Melanoma by Targeting Protein SynthesisTheodosakis N, Micevic G, Langdon CG, Ventura A, Means R, Stern DF, Bosenberg MW. p90RSK Blockade Inhibits Dual BRAF and MEK Inhibitor-Resistant Melanoma by Targeting Protein Synthesis Journal Of Investigative Dermatology 2017, 137: 2187-2196. PMID: 28599981, PMCID: PMC6342201, DOI: 10.1016/j.jid.2016.12.033.
- Aberrant DNA methylation in melanoma: biomarker and therapeutic opportunitiesMicevic G, Theodosakis N, Bosenberg M. Aberrant DNA methylation in melanoma: biomarker and therapeutic opportunities Clinical Epigenetics 2017, 9: 34. PMID: 28396701, PMCID: PMC5381063, DOI: 10.1186/s13148-017-0332-8.
- Attenuation of genome-wide 5-methylcytosine level is an epigenetic feature of cutaneous malignant melanomasMicevic G, Theodosakis N, Taube JM, Bosenberg MW, Rodi N. Attenuation of genome-wide 5-methylcytosine level is an epigenetic feature of cutaneous malignant melanomas Melanoma Research 2017, 27: 85-96. PMID: 27997431, PMCID: PMC5812886, DOI: 10.1097/cmr.0000000000000315.
- The YUMM lines: a series of congenic mouse melanoma cell lines with defined genetic alterationsMeeth K, Wang JX, Micevic G, Damsky W, Bosenberg MW. The YUMM lines: a series of congenic mouse melanoma cell lines with defined genetic alterations Pigment Cell & Melanoma Research 2016, 29: 590-597. PMID: 27287723, PMCID: PMC5331933, DOI: 10.1111/pcmr.12498.
- Stereotactic Ablative Radiation Therapy Combined With Immunotherapy for Solid TumorsBrooks ED, Schoenhals JE, Tang C, Micevic G, Gomez DR, Chang JY, Welsh JW. Stereotactic Ablative Radiation Therapy Combined With Immunotherapy for Solid Tumors The Cancer Journal 2016, 22: 257-266. PMID: 27441745, PMCID: PMC5812885, DOI: 10.1097/ppo.0000000000000210.
- Genome-wide characterization of human L1 antisense promoter-driven transcriptsCriscione SW, Theodosakis N, Micevic G, Cornish TC, Burns KH, Neretti N, Rodić N. Genome-wide characterization of human L1 antisense promoter-driven transcripts BMC Genomics 2016, 17: 463. PMID: 27301971, PMCID: PMC4908685, DOI: 10.1186/s12864-016-2800-5.
- Cell and Tissue DisplayTheodosakis N, Micevic G, Bosenberg MW, Rodić N. Cell and Tissue Display Journal Of Histochemistry & Cytochemistry 2016, 64: 403-411. PMID: 27270967, PMCID: PMC4931762, DOI: 10.1369/0022155416651065.
- Integrative discovery of CD98 as a melanoma biomarkerTheodosakis N, Micevic G, Sharma R, Baras AS, Lazova R, Bosenberg MW, Rodić N. Integrative discovery of CD98 as a melanoma biomarker Pigment Cell & Melanoma Research 2016, 29: 385-387. PMID: 26850337, DOI: 10.1111/pcmr.12464.
- Multilevel Genomics-Based Taxonomy of Renal Cell CarcinomaChen F, Zhang Y, Şenbabaoğlu Y, Ciriello G, Yang L, Reznik E, Shuch B, Micevic G, De Velasco G, Shinbrot E, Noble MS, Lu Y, Covington KR, Xi L, Drummond JA, Muzny D, Kang H, Lee J, Tamboli P, Reuter V, Shelley CS, Kaipparettu BA, Bottaro DP, Godwin AK, Gibbs RA, Getz G, Kucherlapati R, Park PJ, Sander C, Henske EP, Zhou JH, Kwiatkowski DJ, Ho TH, Choueiri TK, Hsieh JJ, Akbani R, Mills GB, Hakimi AA, Wheeler DA, Creighton CJ. Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma Cell Reports 2016, 14: 2476-2489. PMID: 26947078, PMCID: PMC4794376, DOI: 10.1016/j.celrep.2016.02.024.
- DNMT3b Modulates Melanoma Growth by Controlling Levels of mTORC2 Component RICTORMicevic G, Muthusamy V, Damsky W, Theodosakis N, Liu X, Meeth K, Wingrove E, Santhanakrishnan M, Bosenberg M. DNMT3b Modulates Melanoma Growth by Controlling Levels of mTORC2 Component RICTOR Cell Reports 2016, 14: 2180-2192. PMID: 26923591, PMCID: PMC4785087, DOI: 10.1016/j.celrep.2016.02.010.
- Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell ResponsesHo PC, Bihuniak JD, Macintyre AN, Staron M, Liu X, Amezquita R, Tsui YC, Cui G, Micevic G, Perales JC, Kleinstein SH, Abel ED, Insogna KL, Feske S, Locasale JW, Bosenberg MW, Rathmell JC, Kaech SM. Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses Cell 2015, 162: 1217-1228. PMID: 26321681, PMCID: PMC4567953, DOI: 10.1016/j.cell.2015.08.012.
- BRAF Inhibition Decreases Cellular Glucose Uptake in Melanoma in Association with Reduction in Cell VolumeTheodosakis N, Held MA, Marzuka-Alcala A, Meeth KM, Micevic G, Long GV, Scolyer RA, Stern DF, Bosenberg MW. BRAF Inhibition Decreases Cellular Glucose Uptake in Melanoma in Association with Reduction in Cell Volume Molecular Cancer Therapeutics 2015, 14: 1680-1692. PMID: 25948295, PMCID: PMC4497841, DOI: 10.1158/1535-7163.mct-15-0080.
- mTORC1 Activation Blocks Braf V600E -Induced Growth Arrest but Is Insufficient for Melanoma FormationDamsky W, Micevic G, Meeth K, Muthusamy V, Curley DP, Santhanakrishnan M, Erdelyi I, Platt JT, Huang L, Theodosakis N, Zaidi MR, Tighe S, Davies MA, Dankort D, McMahon M, Merlino G, Bardeesy N, Bosenberg M. mTORC1 Activation Blocks Braf V600E -Induced Growth Arrest but Is Insufficient for Melanoma Formation Cancer Cell 2015, 27: 41-56. PMID: 25584893, PMCID: PMC4295062, DOI: 10.1016/j.ccell.2014.11.014.
- Mitochondrial function in melanomaTheodosakis N, Micevic G, Kelly DP, Bosenberg M. Mitochondrial function in melanoma Archives Of Biochemistry And Biophysics 2014, 563: 56-59. PMID: 24997363, DOI: 10.1016/j.abb.2014.06.028.