Oncostatin M Receptor in Pancreatic Adenocarcinoma

Pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer, carries a 5-year mortality rate of 89%. Incidence and mortality from PDAC is rising, such that PDAC will become the second leading cause of cancer deaths in the US by 2040. Despite a robust increase in PDAC research, clinical progress has been slow and still reliant on surgery and cytotoxic therapies, with approved targeted therapies against actionable mutations relevant only to a sliver of patients and virtually no success using immune checkpoint inhibitors (ICI) PDAC. PDAC has a highly desmoplastic stroma that promotes tumor survival and treatment resistance. Here we show that Oncostatin M helps orchestrate this malignant microenvironment of PDAC. OSM belongs to the Interleukin- 6 (IL-6) family and signaling through OSMR and the common receptor, IL6ST/GP130. OSM over-expression studies in cell lines showed that OSM promotes a stem cell phenotype in pancreatic cancer cells (PCCs). Recently it was shown that macrophage OSM signals on fibroblasts to promote PDAC growth and metastasis through heterotypic fibroblast-tumor-macrophage cytokine crosstalk. Our data point to an additional role of OSMR in PCCs. High OSMR expression in PDAC tumors associates to poor prognosis. We show OSM is feed forward, with OSM inducing OSMR in both PCCs and tumor fibroblasts. OSM stimulation of PCCs induced cytokine signaling and changed stem cell, epithelial-to-mesenchymal, and metabolic pathways. OSM caused compaction of PCC/fibroblast spheroids and altered PCC and fibroblast size, shape, and motility. Orthotopic implantation of tumor cells showed that host OSM promotes desmoplasia and tumor pathogenesis and that OSMR depletion in PCCs dramatically reduces tumor growth. Thus, our studies point to an essential role for host-derived OSM signaling on OSMR in tumor cells, complementing prior knowledge on its role in fibroblasts and strengthening the case for targeting OSMR in pancreatic cancer. Based upon these considerable data, we hypothesize that OSMR signaling in PCCs promotes an aggressive, metastatic phenotype and a compacted and immune incompetent microenvironment through both cell autonomous and non- autonomous mechanisms. Blocking OSMR signaling in tumors should result in less aggressive PDAC phenotypes and promote response to therapy. We will test this hypothesis through mechanistic and therapeutic studies in mouse models and by interrogating human specimens using complementary genomics approaches. AIM 1: Define functions of pancreatic cancer cell (PCC) OSMR in the tumor microenvironment and metastasis. AIM 2: Determine the importance of PCC OSMR in response to chemotherapy and immunotherapy. AIM 3: Define the tumor microenvironment and immune contexture and clinical outcomes associated with PCC OSMR expression in PDAC tumors.