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Fibroblast orchestration of the immune response in pancreatic cancer

胰腺癌免疫反应的成纤维细胞协调

基本信息

批准号：
10516238
负责人：
Howard C Crawford
金额：
$ 84.43万
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：
2022-09-19 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10516238
关键词：
Address Affect African American Area Atlas of Cancer Mortality in the United States Biological Cancer Etiology Cells Cessation of life Characteristics Chemoresistance Classification Coculture Techniques Conflict (Psychology)Cytokine Gene Data Desmoplastic Diagnosis Disease Epithelial Ethnic Origin Evolution Excision Fibroblasts Gene Expression Profile Genes Genetic Transcription Genetically Engineered Mouse Growth Health system Heterogeneity Histologic Human Immune Immune response In Vitro Infiltration Inflammatory Investigation KRAS oncogenesis KRAS2 gene Ligands Light Literature Malignant Neoplasms Malignant neoplasm of pancreas Maps Mediating Mesenchymal Metabolic Michigan Minority Modeling Mus Mutation Nature Oncogenic Operative Surgical Procedures Organoids Pancreas Patients Population Race Recurrence Regulation Role STAT3 gene Signal Pathway Signal Transduction Target Populations Testing Tumor Subtype Tumor Suppressor Proteins Tumor Volume Tumor-associated macrophages Tumor-infiltrating immune cells Universities Work advanced disease base cancer cell cancer therapy carcinogenesis cytokine human disease in vivo molecular subtypes mutant neoplastic cell new therapeutic target novel therapeutic intervention pancreatic cancer model pancreatic cancer patients pancreatic tumorigenesis patient population programs racial and ethnic standard of care therapy resistant tumor

项目摘要

Pancreatic cancer is a deadly malignancy, direly in need of new therapeutic approaches. Pancreatic cancer is characterized by extensive accumulation of a fibroinflammatory stroma, containing abundant fibroblasts. Long believed to be a uniform cell population, fibroblasts have emerged as a heterogeneous and functionally important component of the tumor. Yet, the literature on fibroblasts in pancreatic cancer is controversial, with studies supporting both a pro- and an anti-tumor role. Our preliminary data show that oncogenic KRAS, a hallmark mutation of pancreatic cancer, expressed in tumor cells extrinsically reprograms the transcriptional program of fibroblasts. Further, continuous expression of epithelial oncogenic Kras is required to maintain expression of a panel of inflammatory cytokines in fibroblasts. Unlike mouse tumors, human pancreatic cancer is highly heterogeneous in terms of genetic alterations and histological characteristics of cancer cells. How fibroblasts are reprogrammed in the context of different types of human pancreatic cancer and how they contribute to carcinogenesis is unclear. Lastly, most in depth studies on pancreatic cancer are based on largely White patient populations, while the disease is equally prevalent in all race groups. The University of Michigan/Henry Ford Health System team together has access to a large patient volume, diverse patient populations (with 30% HFHS patients being African American), and the skillset to characterize and functionally assess fibroblasts on pancreatic cancer. We will map fibroblast heterogeneity across tumors in a diverse patient population. We will evaluate whether fibroblast heterogeneity correlates with different subtypes of tumor cells (classified as classical and mesenchymal). We will further take advantage of the genetically engineered mouse models available in our group to target fibroblast reprogramming at different stages of carcinogenesis. Overall, our work will shed light on the regulation and function of pancreatic CAFs and open the way for new therapeutic approaches targeting this population.

胰腺癌是一种致命的恶性肿瘤，迫切需要新的治疗方法。胰腺癌是以广泛堆积的纤维炎性间质为特征，含有丰富的成纤维细胞。长成纤维细胞被认为是一个统一的细胞群体，已经成为一种异质的、具有重要功能的细胞肿瘤的组成部分。然而，关于成纤维细胞在胰腺癌中的研究文献是有争议的。既支持促肿瘤作用，也支持抗肿瘤作用。我们的初步数据显示，致癌的KRAS是一个标志胰腺癌的突变，在肿瘤细胞中表达，外源性地重新编程转录程序成纤维细胞。此外，上皮性致癌kras的持续表达需要维持a的表达。成纤维细胞中的炎性细胞因子群。与老鼠肿瘤不同，人类胰腺癌的发病率很高。在肿瘤细胞的遗传改变和组织学特征方面的异质性。成纤维细胞是如何在不同类型的人类胰腺癌的背景下重新编程及其对致癌机制尚不清楚。最后，大多数关于胰腺癌的深入研究都是基于大部分白人患者虽然这种疾病在所有种族群体中同样普遍，但在所有人群中都是如此。密歇根大学/亨利·福特卫生系统团队共同接触到大量不同的患者群体(30%的HFHS 患者是非裔美国人)，以及对成纤维细胞进行表征和功能评估的技能胰腺癌。我们将绘制不同患者群体中肿瘤间成纤维细胞的异质性图谱。我们会评估成纤维细胞的异质性是否与不同的肿瘤细胞亚型(归类为经典肿瘤细胞)相关和间充质细胞)。我们将进一步利用我们的小组针对不同癌变阶段的成纤维细胞重编程。总体而言，我们的工作将揭示胰腺CAF的调节和功能及其靶向治疗开辟新途径这群人。