Abstract 1841: Dissecting gene expression programs that define tumor aggression and patient outcome in pancreatic cancer

Abstract By the year 2020, pancreatic cancer (PDAC) is projected to be the second leading cause of cancer deaths in the United States. Current systemic therapies offer limited survival advantages in subgroups of patients, suggesting underlying biological differences in this deadly cancer. Our lab has recently identified keratin-17 (K17) gene expression as a prognostic and predictive biomarker in PDAC. Furthermore, we found that K17 acts as an oncoprotein by promoting degradation of tumor suppressor p27KIP1, while knockdown of K17 limits tumor size and sensitizes cancer cells to chemotherapy agents. Together, these findings suggest that targeting K17 expression in PDACs may increase patient survival and response to treatment. The factors that lead to increased K17 gene expression in only a subset of PDAC cases, however, are unknown. K17 is expressed in embryonic ectoderm and aberrantly induced in keratinocytes from psoriasis patients through paracrine signaling from the microenvironment. To determine how K17 gene expression is upregulated in PDAC, we tested the effects of two major contributing factors in PDAC pathogenesis: driver mutations and inflammatory mediators present in tumor microenvironment. Using in vitro and in vivo loss- and gain-of function approaches, we modulated oncogene expression in and performed acute cytokine treatments on cells to test for changes in K17 gene expression. K17 expression was evaluated by qRT-PCR and western blot. We found that forced expression of oncogenes like KRASG12D, Q61K or TP53R248W significantly increase K17 expression, yet these cell-autonomous factors are not sufficient to explain K17 gene expression in PDACs. In addition, we found that pro-inflammatory cytokines, typically released by helper T cells, induce a strong increase in K17 gene expression. Together these findings suggest that K17 gene expression across otherwise clinically identical PDAC cases may be explained by early transformation events and maintained by positive feedback loops associated with patient specific adaptive immune response. Ongoing studies are seeking to test the combined effects of genetic and paracrine events in K17 expression, and understand the signaling pathways and transcription factors downstream of these inducing factors. Ultimately, insight into the mechanisms that mediate K17 overexpression in PDACs could help guide future research to develop K17 as a potential therapeutic target. Citation Format: Danielle J. Fassler, Luisa F. Escobar-Hoyos, Kenneth R. Shroyer. Dissecting gene expression programs that define tumor aggression and patient outcome in pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1841.