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，非常需要新的治疗方法。胰腺癌是其特征是含有丰富成纤维细胞的纤维炎性基质的广泛积累。长的据信是一个均匀的细胞群，成纤维细胞已成为异质性且功能上很重要的成纤维细胞肿瘤的成分。然而，关于胰腺癌成纤维细胞的文献是有争议的支持亲肿瘤和抗肿瘤作用。我们的初步数据表明，癌症Kras是一个标志在肿瘤细胞中表达的胰腺癌突变外在重新编程成纤维细胞。此外，需要连续表达上皮致癌性KRAS以维持A的表达成纤维细胞中的炎症细胞因子面板。与小鼠肿瘤不同，人胰腺癌高度高就癌细胞的遗传改变和组织学特征而异质。成纤维细胞是多么的在不同类型的人类胰腺癌的背景下重新编程致癌作用尚不清楚。最后，大多数关于胰腺癌的深度研究基于白人患者种群，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获得大量患者量，多样化的患者人群（有30％的HFHS 患者是非裔美国人），以及在功能上表征和功能评估成纤维细胞的技能胰腺癌。我们将在多样化的患者人群中绘制跨肿瘤的成纤维细胞异质性。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（被分类为经典和间充质）。我们将进一步利用我们的基因工程鼠标模型在癌变的不同阶段靶向成纤维细胞重编程。总的来说，我们的工作将浮出水面关于胰腺CAF的调节和功能，并为针对新的治疗方法开辟道路这个人口。