Project Title: Elucidating Kras-driven immune infiltration and function in pancreatic cancer Pancreatic Ductal Adenocarcinoma (PDA) is a lethal malignancy with a 5-year survival rate of 9%. PDA is characterized by a dense stroma with a heterogeneous population of fibroblasts and infiltrating immune cells. The cross-talk between tumor cells, fibroblasts, and immune cells leads to a highly immunosuppressive microenvironment. However, the mechanisms underlying the cross-talk is poorly understood. Mutations in the Kras oncogene are the main drivers of PDA and are found in more than 90% of human pancreatic tumor samples. Kras activates different downstream signaling pathways, including MAPK, PI3K/AKT and JAK/STAT signaling. My preliminary data shows that Kras modulates the immune cells recruitment and function. The goal of this proposal is to identify the downstream signaling pathways used by oncogenic Kras-expressing epithelial cells to polarize macrophages to an immunosuppressive phenotype. Further, preliminary data that I generated shows that the JAK/STAT signaling pathway is active in the stroma, while MAPK and PI3K are predominantly epithelial. Specifically, macrophages have active JAK/STAT signaling pathway. Thus, I will investigate the role of JAK/STAT3 signaling pathway in driving immunosuppression in macrophages. I hypothesize that oncogenic Kras (Kras*) expression in tumor cells drives immunosuppression and that targeting JAK/STAT pathway in macrophages will lead to reversion of the immunosuppressive phenotype aiding in the treatment of pancreatic cancer. To study the three Kras* downstream signaling pathways and how they are involved in macrophage polarization I will use an in vitro co-culture of tumor cells and bone marrow-derived macrophages. I will use shRNA to downregulate expression of the main component of each pathway in tumor cells and dissect the crosstalk using protein and RNA analysis. To understand the role of JAK/STAT in the polarization of myeloid cells and consequently in tumor growth, I will use a genetically engineered mouse model that depletes STAT3 specifically in myeloid cells, specially macrophages. These studies will provide a comprehensive view on how Kras* regulates the tumor microenvironment.
Pancreatic cancer is a lethal disease characterized by an extensive fibroinflammatory response. The lethality of this disease is associated to the immunosuppressive microenvironment, which is in part regulated by oncogenic Kras-expressing epithelial cells. I propose to study the mechanisms of myeloid cell polarization by oncogenic Kras-expressing cells during pancreatic carcinogenesis to identify new targets to improve the survival to pancreatic cancer.
