Defining epigenetic signaling to reshape pancreatic tumor microenvironment

定义表观遗传信号重塑胰腺肿瘤微环境

基本信息

批准号：
10666682
负责人：
Jiaqi Shi
金额：
$ 45.59万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10666682
关键词：
Activins Animal Model Biological Assay CRISPR/Cas technology Cancer Etiology Cell Line Cells Cessation of life ChIP-seq Characteristics Coculture Techniques Cytometry Data Development Enhancers Enzymes Epigenetic Process Failure Fibroblasts Future Genetic Genetic Transcription Goals Grant Immune Immunohistochemistry Immunologics Immunotherapy Infiltration Inflammatory KRAS2 gene Knock-out Knowledge Ligands Luciferases Macrophage Malignant Neoplasms Malignant neoplasm of pancreas Mediating Modeling Molecular Mutation Myeloid-derived suppressor cells Neoadjuvant Therapy Pancreas Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Preclinical Testing Prognosis Public Health Regulation Reporter Research Resistance Role Secondary to Shapes Signal Transduction T cell infiltration T-Cell Activation T-Lymphocyte Technology Testing Transcriptional Regulation Tumor-associated macrophages Up-Regulation Xenograft procedure activin A cancer cell cancer genetics cell behavior clinical development cofactor cytokine effector T cell epigenetic regulation histone modification improved innovation knock-down loss of function mutation mouse model neoplastic cell novel pancreas development pancreatic cancer patients pancreatic ductal adenocarcinoma cell pancreatic neoplasm preclinical development programs protein expression receptor response single-cell RNA sequencing therapy resistant three dimensional cell culture three-dimensional modeling transcription factor treatment strategy tumor tumor growth tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

PROJECT SUMMARY/ABSTRACT The 5-year survival of pancreatic cancer patients remains at 10% primarily due to the tumor resistance to standard chemo and immunotherapies. The profound immunosuppressive tumor microenvironment contributes to treatment resistance. Notably, 82% of the neoadjuvant-treated pancreatic cancers carry loss of function mutations for KMT2D, a histone modification enzyme. Epigenetics is known to impact cancer cell behavior. However, how tumor cell-intrinsic epigenetic alterations modulate the pancreatic tumor microenvironment remains elusive. The long-term goal is to develop new treatments to convert pancreatic cancer to an immunologically hot tumor and improve the efficacy of immunotherapy and patient survival. The overall objectives in this application are to 1) determine the impact of KMT2D signaling on the tumor microenvironment and 2) characterize the mechanisms by which KMT2D regulates activin A expression. The central hypothesis is that upregulation of activin A upon KMT2D loss in pancreatic cancer reprograms cancer- associated fibroblasts and immune cells to promote a pro-tumoral immunosuppressive microenvironment. The rationale for this project is that the knowledge of the mechanisms by which KMT2D regulates the tumor microenvironment will pave the way for future preclinical and clinical development of new strategies to treat pancreatic cancer. The central hypothesis will be tested by pursuing three specific aims: 1) Elucidate the impact of KMT2D signaling on the immune composition in the tumor microenvironment; 2) Define the regulation of heterogeneous cancer-associated fibroblasts by KMT2D signaling; and 3) Determine the molecular mechanisms of activin A regulation by KMT2D in pancreatic cancer. Under the first and second aims, we will use our established pancreatic cancer genetic mouse models with pancreas-specific inactivation of KMT2D to determine the impact of KMT2D signaling on the differentiation and activation of cancer- associated fibroblasts, macrophages, and T cells, and ligand-receptor interactions in the tumor microenvironment and the underlying mechanisms. Single-cell RNA sequencing technology, mass cytometry, and multiplex fluorescent immunohistochemistry will be used. For the third aim, we will characterize the interactions between KMT2D and co-factors and the mechanisms of KMT2D-mediated regulation of activin A transcription and enhancer activity using ChIP-seq, BruUV-seq, and functional luciferase reporter assays. The research proposed in this application is innovative because it focuses on a novel concept that epigenetic signaling from tumor cells remodels the tumor microenvironment and contributes to cancer progression and uses state-of-the-art animal models and approaches. The proposed research is significant because it will shed light on the mechanism of transcriptional regulation by KMT2D in pancreatic cancer and the effect of KMT2D signaling on pancreatic tumor microenvironment, which will set the stage for future preclinical and clinical development of new tumor microenvironment-targeting treatment strategies.

项目概要/摘要胰腺癌患者的5年生存率仍维持在10%，主要是由于肿瘤的耐药性标准化疗和免疫疗法。深刻的免疫抑制肿瘤微环境有助于对治疗的抵抗力。值得注意的是，82% 的新辅助治疗胰腺癌伴有功能丧失 KMT2D（一种组蛋白修饰酶）的突变。众所周知，表观遗传学会影响癌细胞的行为。然而，肿瘤细胞内在的表观遗传改变如何调节胰腺肿瘤微环境仍然难以捉摸。长期目标是开发新的治疗方法将胰腺癌转变为癌症免疫热肿瘤并提高免疫治疗的疗效和患者的生存率。整体本申请的目标是 1) 确定 KMT2D 信号传导对肿瘤的影响微环境和 2) 表征 KMT2D 调节激活素 A 表达的机制。这中心假设是胰腺癌中 KMT2D 缺失后激活素 A 的上调会重新编程癌症相关的成纤维细胞和免疫细胞，以促进促肿瘤免疫抑制微环境。这该项目的基本原理是了解 KMT2D 调节肿瘤的机制微环境将为未来临床前和临床开发新的治疗策略铺平道路胰腺癌。将通过追求三个具体目标来检验中心假设：1）阐明 KMT2D信号对肿瘤微环境中免疫成分的影响； 2) 定义通过 KMT2D 信号传导调节异质性癌症相关成纤维细胞； 3) 确定 KMT2D 在胰腺癌中调节激活素 A 的分子机制。在第一个和第二个下我们的目标是，我们将使用我们已建立的具有胰腺特异性失活的胰腺癌遗传小鼠模型 KMT2D 以确定 KMT2D 信号传导对癌症分化和激活的影响- 肿瘤中相关的成纤维细胞、巨噬细胞和 T 细胞以及配体-受体相互作用微环境和潜在机制。单细胞RNA测序技术、质谱流式分析、并将使用多重荧光免疫组织化学。对于第三个目标，我们将描述 KMT2D 与辅因子之间的相互作用以及 KMT2D 介导的激活素 A 调节机制使用 ChIP-seq、BruUV-seq 和功能性荧光素酶报告基因检测进行转录和增强子活性。这该申请中提出的研究具有创新性，因为它关注的是表观遗传的新概念来自肿瘤细胞的信号传导重塑肿瘤微环境并有助于癌症进展和使用最先进的动物模型和方法。拟议的研究意义重大，因为它将摆脱揭示KMT2D在胰腺癌中的转录调控机制及KMT2D的作用胰腺肿瘤微环境中的信号传导，这将为未来的临床前和临床奠定基础开发新的肿瘤微环境靶向治疗策略。