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Origins and functions of pancreatic cancer-associated fibroblasts

胰腺癌相关成纤维细胞的起源和功能

基本信息

批准号：
10611388
负责人：
Mara H. Sherman
金额：
$ 37.96万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
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：
2023-01-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10611388
关键词：
Ablation Acceleration Address Biology Cancer Etiology Cell Differentiation process Cell physiology Cells Cellular Metabolic Process Cessation of life Clinic Complex Data Desmoplastic Development Disease Epithelium Evolution Extracellular Matrix Fibroblasts Gene Expression Profiling Genetic Genetic Transcription Genotype Goals Heterogeneity Immunotherapy Inflammatory Lipids Malignant Neoplasms Malignant neoplasm of pancreas Minor Modeling Mutation Pancreas Pancreatic Ductal Adenocarcinoma Patients Phenotype Population Population Heterogeneity Prognosis Proliferating Property Reaction Regulation Reporter Reporting Resistance Role Route Sampling Solid Neoplasm Source Stromal Cells TP53 gene Testing Therapeutic Intervention Time Tissues Tumor Immunity Tumor Promotion Tumor Tissue Tumor Volume United States Work cancer cell cell behavior cell type chemotherapy density disease phenotype effective therapy experimental study gain of function mutation immune checkpoint blockade immunoregulation improved in vivo mortality mouse model neoplastic cell novel novel therapeutic intervention novel therapeutics pancreatic cancer cells pancreatic ductal adenocarcinoma cell pancreatic neoplasm pancreatic stellate cell pancreatic tumorigenesis pharmacologic programs rational design standard of care stellate cell targeted treatment therapeutic target therapy resistant transdifferentiation treatment response tumor tumor growth tumor microenvironment tumor progression

项目摘要

PROJECT SUMMARY/ABSTRACT The mechanisms underlying evolution of tumor-associated stroma remain poorly understood. In solid tumors featuring a prominent stromal reaction, an improved understanding of the functions and origins of abundant stromal cell types may facilitate the development of new and effective therapies. Pancreatic ductal adenocarcinoma (PDAC) is the quintessence of a fibro-inflammatory malignancy, with 50-90% of tumor volume occupied by a dense, desmoplastic stroma. Cancer-associated fibroblasts (CAFs) are the key cell type which drives the stromal reaction in PDAC, and recent reports suggest that stromal CAFs represent a heterogeneous population of cells from diverse origins, potentially including cell types which support and others which suppress tumor growth. Pancreatic stellate cells (PSCs) are lipid-storing cells in healthy pancreas which can transdifferentiate to an activated CAF phenotype. PSCs have been suggested as the predominant source of fibroblasts in the PDAC tumor microenvironment. However, proper lineage tracing studies have never been performed, such that the relative contribution and specific functions of PSCs in the tumor microenvironment are unknown. Here we will take advantage of a novel mouse model we have developed to track PSC differentiation and function during pancreatic tumor progression in vivo. We hypothesize that PSC-derived fibroblasts in the PDAC microenvironment are a pro-inflammatory and tumor-supportive subset of PDAC CAFs, and thus represent a viable therapeutic target. Our preliminary data support the notion that PSCs contribute to only a subset of the CAF population in the tumor microenvironment, and the functions of these distinct populations are entirely unknown. Our data to date also highlight a potential role for genetic alterations in the epithelial compartment in orchestration of stromal fibroblast evolution. PDAC stromal heterogeneity and functional significance will be interrogated with the following specific aims. Aim 1: Determine the role of PSC- derived CAFs in pancreatic tumorigenesis. A novel mouse model will be used to ablate PSC-derived CAFs for the first time and analyze the impact on tumor growth, survival, and organization of the tumor microenvironment. Aim 2: Assess the consequence of tumor genotype in pancreatic cancer stromal evolution. Motivated by preliminary data, we will use our reporter mouse model and patient samples to analyze the interaction between p53 status in tumor cells and stromal CAF evolutionary routes, with important potential implications for tumor phenotype and therapy responses. Aim 3: Define the role of PSC-derived CAFs in therapy response and resistance. As PSC-derived CAFs express a transcriptional program associated with resistance to chemotherapy and immunotherapy, we will determine the effect of these CAFs on treatment response in vivo. These findings will shed light on mechanisms and consequences of stromal evolution during pancreatic tumorigenesis, and potentially identify distinct CAF populations of relevance in additional solid tumors.

项目总结/文摘