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。胰腺癌是其特征是纤维炎症基质的广泛积累，含有丰富的成纤维细胞。长的成纤维细胞被认为是统一的细胞群，但现已成为异质且具有重要功能的细胞肿瘤的组成部分。然而，有关胰腺癌成纤维细胞的文献存在争议，研究表明支持促肿瘤和抗肿瘤作用。我们的初步数据表明，致癌 KRAS 是一个标志胰腺癌的突变，在肿瘤细胞中表达，从外部重新编程转录程序成纤维细胞。此外，需要上皮致癌 Kras 的持续表达来维持成纤维细胞中的一组炎症细胞因子。与小鼠肿瘤不同，人类胰腺癌的发病率很高癌细胞的遗传改变和组织学特征具有异质性。成纤维细胞是怎样的在不同类型的人类胰腺癌的背景下重新编程以及它们如何促进致癌机制尚不清楚。最后，大多数对胰腺癌的深入研究主要基于白人患者人群中，而这种疾病在所有种族群体中同样普遍。密歇根大学/亨利·福特卫生系统团队共同接触大量患者、多样化患者群体（其中 30% 为 HFHS）患者是非裔美国人），以及表征和功能评估成纤维细胞的技能胰腺癌。我们将绘制不同患者群体肿瘤中成纤维细胞异质性的图谱。我们将评估成纤维细胞异质性是否与肿瘤细胞的不同亚型相关（分类为经典和间充质）。我们将进一步利用我们的基因工程小鼠模型小组针对癌发生不同阶段的成纤维细胞重编程。总体而言，我们的工作将阐明胰腺 CAF 的调节和功能，为新的靶向治疗方法开辟道路这个人口。