U01CA274154

Fibroblast Orchestration of the Immune Response in Pancreatic Cancer

Pancreatic cancer is a deadly malignancy that is in dire need of new therapeutic approaches. It is characterized by extensive accumulation of a fibroinflammatory stroma, containing abundant fibroblasts. Fibroblasts, once believed to be a uniform cell population, have now emerged as a heterogeneous and functionally important component of the tumor. However, 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. Furthermore, 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 in 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 cancer-associated fibroblasts (CAFs) and open the way for new therapeutic approaches targeting this population.

Regents Of The University Of Michigan

TO PROVIDE FUNDAMENTAL INFORMATION ON THE CAUSE AND NATURE OF CANCER IN PEOPLE, WITH THE EXPECTATION THAT THIS WILL RESULT IN BETTER METHODS OF PREVENTION, DETECTION AND DIAGNOSIS, AND TREATMENT OF NEOPLASTIC DISEASES. CANCER BIOLOGY RESEARCH INCLUDES THE FOLLOWING RESEARCH PROGRAMS: CANCER CELL BIOLOGY, CANCER IMMUNOLOGY, HEMATOLOGY AND ETIOLOGY, DNA AND CHROMOSOMAL ABERRATIONS, TUMOR BIOLOGY AND METASTASIS, AND STRUCTURAL BIOLOGY AND MOLECULAR APPLICATIONS.

93.396 - Cancer Biology Research

National Cancer Institute (NCI) [HHS - NIH]

Michigan United States

State-Wide

Pancreatic Ductal Adenocarcinoma (PDAC) Stromal Reprogramming Consortium (PSRC) (U01 Clinical Trial Not Allowed) (RFA-CA-21-041)

Amendment Since initial award the total obligations have increased 191% from $844,294 to $2,459,943.