Single-Cell Dissection of Chromatin Accessibility and Oncogenic Regulators in Pleural Mesothelioma
Abstract
This proposal is for the fiscal year 2022 Peer Reviewed Cancer Research Program (PRCRP) Topic Area of Mesothelioma. While most cancers are thought to result from accumulations of DNA mutations, malignant pleural mesothelioma (MPM) exhibits a lower number of point mutations in aggregate and particularly at well-studied oncogenes than most other cancer types, including lung cancers. This makes it challenging to find targeted therapies for MPM that can counteract the effect of commonly encountered oncogenes. Meanwhile, changes to the epigenome and chromatin, or proteins and macromolecules that package and maintain the DNA, have been associated with asbestos exposure and MPM progression. This highlights the importance of improving our understanding of the epigenetic alterations that leads to MPM to identify more effective therapies and biomarkers of response. Towards this goal, we will use state-of-the-art single-cell epigenetic technologies on clinical samples from 20 treatment-naive MPM patients, which would allow us to construct the first chromatin accessibility map for each cell population in the MPM tumor microenvironment. Such a high-resolution perspective will enable us to develop improved computational methods for discovery of the key transcriptional mechanisms and genomic regions, such as super-enhancers, that are dysregulated in each specific cell subpopulation, that likely promote tumor survival and/or immune evasion, and that can form the basis of novel epigenetic-based or combination therapies in MPM. We will validate the functional role of putative therapeutic targets using small molecule and genetic perturbations in patient-derived cell line and organoid models. The proposed study seeks to identify the epigenetic mechanisms and genomic regions in different cell populations of the MPM tumor microenvironment that likely contribute to tumor progression and survival. In the short term, this study will improve understanding of the epigenetic landscape in MPM by constructing the first single-cell map of chromatin accessibility in each cell population, which will serve as a valuable reference for the MPM clinical and research community. Deeper understanding of the regulatory mechanisms and genomic regions that are commonly dysregulated in each MPM cell population will suggest new therapeutic pathways to target with existing small molecule inhibitors and/or emerging CRISPR-based gene therapies. We will also develop a new computational method for detecting key genomic regions called super-enhancers, which have been shown to be effective therapeutic targets in other cancer types (e.g., leukemia) as well as predictive biomarkers of drug sensitivity and response. Our computational method will be made available to the research community upon publication and can be applied for identification of super-enhancers and therapeutic targets in other cancer types. In the near term, our clinically minded team at the Mount Sinai Health System is well positioned to initiate clinical trials aimed at testing the most promising therapeutic target based on our computational predictions and functional validations in this study. Our proposal primarily seeks to address the PRCRP Overarching Challenge to transform cancer treatment through the identification of novel biomarkers and new targets especially for advanced disease. Moreover, our identification of novel regulators and genomic regions responsible for MPM development will identity and understand unique and novel mechanisms behind cancer epigenetics, biological development, etiology, and genetic basis. Advancing understanding to the regulatory regions that promote tumor survival in different cell populations will also uncover novel therapeutic targets that can more effectively synergize with and improve immunotherapy. Our proposal seeks to address the PRCRP Military Health Focus of the gap in effective treatment affecting the health and well-being of military members
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310496
Entities
People
- Alexander Tsankov
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army