Abstract
Abstract The Pancreatic Ductal Adenocarcinoma (PDAC) tumor microenvironment (TME) is comprised of numerous cell types. Among those, cancer associated fibroblasts (CAFs) play roles in tumor development, drug resistance, fibrosis and inflammation. GP130 cytokines, including Interleukin-6 (IL-6) and Leukemia Inhibitory Factor in the TME are implicated in pancreatic cancer progression and drug resistance, but less is known of the other cytokines in this family. Oncostatin M (OSM) enhances tumorigenicity, regulates tissue remodeling, and activates epithelial-to-mesenchymal transition in cancer; however, the functions of OSM in the pancreatic cancer TME and relevant phenotypes in PDAC patients have not been fully elucidated. Staining of murine tumor tissue revealed staining of OSM in tumor cells, and its receptor, OSMR, in tumor cells and fibroblasts. To model the effects of OSM in the TME, we used a spheroid culture system with patient-derived tumor cells (Pa03C cells) and patient-derived pancreatic cancer associated fibroblasts (CAF3 and CAF19) treated with rhOSM. In vitro, OSM promoted activation and proliferation of CAF monocultures, but had no effect on tumor cells. In co-cultures, OSM caused clustering of CAFs, resulting in a denser and more fibrotic spheroid with a network of CAFs clustered tightly around tumor cells. There was no effect of OSM on tumor cells in monoculture, suggesting the effects of OSM are mediated on and through fibroblasts. To study OSM in human PDAC, we used TCGA for expression and correlative gene analysis. OSM expression in tumors did not correlate with survival. In contrast, high expression of OSMR correlated with decreased patient survival (p=0.051). This effect was sex-specific–the top quartile of OSMR expressing tumors associated with median overall survival (OS) of 600 days, while the bottom three quartiles showed OS of 1100 days (p=0.0047). There was no correlation with OSMR expression and survival in female patients. Tumor OSM and OSMR expression were not different between the sexes, however. For OSM, 504 genes correlated positively with r>0.03. For OSMR, 5962 genes correlated with |r|0.3, with OSM identified as an upstream regulator (Z-score 5.770). The top upstream regulators identified in common between the OSM and OSMR correlated genes were lipopolysaccharide (Z-scores 8.408 and 8.556 for OSM and OSMR respectively), TGFB1 (7.562 and 8.799), and TNF (7.397 and 6.813), linking inflammation to fibrosis in the TME. Taken together with data from our functional studies, these data suggest that OSM and OSMR modulate the PDAC tumor microenvironment and disease outcomes in PDAC. More functional investigation is warranted for this important pathway. Citation Format: Daenique H. Jengelley, Melissa L. Fishel, Michael Ostrowski, Teresa A. Zimmers. Oncostatin M in pancreatic cancer tumor microenvironment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2644.
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