Epigenetic Regulation of the Melanoma Microenvironment
Abstract
Melanoma is the most lethal skin cancer and when detected at an advanced stage, success of currently available therapies is limited. Immunotherapy reactivates a patient’s own immune system to destroy cancer cells in the body. This represents a breakthrough in melanoma therapy, as it can be curative in some patients. However, not all patients respond to immunotherapy or can develop resistance. Therefore, a better understanding of immune cell regulation in the context of melanoma is critically needed to improve treatments and overall survival. DNA is packaged in the nucleus by a variety of proteins to form chromatin. Chromatin regulators are emerging as promising candidates for cancer therapy because of their broad roles in orchestrating genome function, as well as their frequent alterations in cancer. Among these, a specialized histone called macroH2A functions to suppress melanoma growth and metastasis. We previously found that macroH2A levels are strikingly decreased in advanced melanoma using cells grown in culture and human patient samples. However, it is not clear how macroH2A blocks melanoma development during the tumor evolution. Using novel tools we have created in the laboratory, we propose to study how macroH2A functions in the dynamic process of melanoma development in a mouse model where macroH2A is either present or absent. To this aim, we have generated macroH2A-deficient mice that can be induced to develop melanoma tumors and we found that the immune cells within the tumor, which normally destroy cancer cells, were abnormal. We hypothesize that the absence of macroH2A increases the aggressiveness of melanomas by limiting the activity of the immune system. Using a combination of innovative immunological and chromatin biology approaches, we will characterize how macroH2A loss in melanoma cells renders them invisible to immune cell killing and how macroH2A contributes to the proper training of immune cells to mount an effective response against tumor cells. Thus, our study addresses the Fiscal Year 2019 Melanoma Research Program Focus Areas: Primary Tumor Evolution and Tumor Microenvironment. Ultimately, we will treat mice harboring macroH2A-deficient melanomas with Food and Drug Administration-approved therapies for this tumor type, in order to model how human melanomas with similar characteristics responds to these drugs. In sum, our study will determine whether macroH2A levels can predict the outcome of therapies that unleash the immune system against the tumor, how macroH2A regulates cells of the immune system in response to a tumor, whether macroH2A directly regulates cellular factors that can be targeted with available drugs, and overall, help improve the clinical approaches that leverage the immune system against tumor cells for melanoma patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010803
Entities
People
- Emily Bernstein
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army