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Chromatin and immune regulation of tumor growth and progression

肿瘤生长和进展的染色质和免疫调节

基本信息

批准号：
10744436
负责人：
Emily Lorin Ashkin
金额：
$ 4.92万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-10 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10744436
关键词：
3-Dimensional Antigens Architecture Bar Codes Biological Assay Biological Process Cells Cellular Immunity Characteristics Chromatin Chromatin Loop Chromosome Mapping Complex Cytotoxic T-Lymphocytes Data Dedications Dependence Development Diagnosis Disease Progression Evolution Gene Expression Gene Expression Profile Gene Expression Profiling Genes Genetic Genetically Engineered Mouse Goals Immune Evasion Immune response Immunophenotyping KRAS oncogenesis KRAS2 gene Laboratories Lung Lung Neoplasms Maintenance Malignant neoplasm of lung Malignant neoplasm of pancreas Mediating Mediator Mentors Methodology Molecular Molecular Conformation Mus Pancreatic Ductal Adenocarcinoma Phase Play Positioning Attribute Postdoctoral Fellow Proteins Regulation Research Research Project Grants Role Shapes System T cell response T-Lymphocyte Techniques Time Training Tumor Immunity Tumor Subtype Tumor Suppression Tumor Suppressor Genes Tumor Suppressor Proteins Tumor Volume Tumor stage Work anti-tumor immune response cancer cell cancer type candidate identification cell type chemotherapy cohesin experience experimental study functional genomics gene function high throughput screening immunoregulation in vivo innovation insight lung cancer cell lung tumorigenesis medical specialties mouse model multidisciplinary multiple omics neoplastic cell novel novel strategies pancreatic ductal adenocarcinoma model response tumor tumor growth tumor heterogeneity tumor immunology tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY Lung and pancreatic ductal adenocarcinomas are often diagnosed at very late stages of tumor progression when they are most aggressive and difficult to treat. Currently, very little is known about the characteristics that make up the complex tumor heterogeneity of late-stage tumors and what factors contribute to such changes in cancer cell state and disease progression over time. Investigating how the mechanisms by which these contributing factors impact tumorigenesis and tumor heterogeneity may uncover unappreciated biological processes that control tumor development. The goal of this work is to elucidate the molecular and cellular mechanisms that drive changes in chromatin state and immune response and how they shape tumor heterogeneity and tumor progression. In the F99 phase, I aim to elucidate how a novel tumor suppressor gene constrains lung tumorigenesis. My colleagues and I identified STAG2 as a tumor suppressor in a genetically engineered mouse model of oncogenic KRAS-driven lung cancer. STAG2 is a subunit of one of the two major cohesin complexes, which are implicated in regulating chromatin boundaries and gene expression. However, the mechanism by which Stag2 inactivation drives lung tumor growth is unknown. I performed chromatin accessibility profiling and gene expression analyses on STAG2-proficient and STAG2-deficient mouse lung cancer cells and have unveiled potential mediators of STAG2 function. Based on my analyses, I hypothesize that STAG2 controls genes involved in early stages of tumorigenesis by directly impacting cohesin regulation of 3D chromatin organization. Using chromatin conformation assays, I will assess how STAG2 regulates chromatin at different stages of tumor progression and how Stag2 inactivation drives lung tumorigenesis. Additionally, I will use Tuba-seq to identify key epistatic and downstream mediators of STAG2 tumor suppression and chromatin conformation assays to ascertain the STAG2-mediated mechanisms impacting lung tumor maintenance. In the K00 phase, I aim to elucidate how cancer cell state shapes pancreatic ductal adenocarcinoma (PDAC) response to T-cell mediated anti-tumor immunity. PDAC subpopulations with distinct transcriptional profiles, stromal composition, and response to chemotherapy have been previously established. However, it remains unknown whether these tumor subtypes harbor differential response to T-cell mediated immunity. To investigate how cancer cell state shapes PDAC progression by enabling evasion of cytotoxic T cell responses, I will leverage PDAC mouse models that enable the initiation of cytotoxic T cell responses at different stages of tumor progression using an inducible mouse model T cell antigen. Using longitudinal multi-omics, immunophenotyping, and tumor volume analyses, I will investigate how aspects of tumor heterogeneity contribute to mechanisms of immune evasion at various stages of tumor progression, identify key mechanistic drivers, and thus uncover novel strategies to enhance anti- tumor immune responses. Together, this body of work will elucidate principles of chromatin regulation and tumor heterogeneity that contribute to progression and immune response in lung and pancreas cancers.

项目总结