Impact of Inflammatory Pathway in Tumor Stroma on Pancreatic Cancer Growth

Abstract public domain (NIH RePORTER)

Despite recent advances, pancreatic cancer patients continue to have dismal outcomes thereby underscoring the need for development of new therapeutic strategies. Recently, there has been a resurgence in understanding the role played by stroma in supporting tumor growth and the stroma- cancer cell cross talk continues to be a promising anti-cancer target. Previous research has shown that NFκB, the master regulator of inflammation, is overexpressed in various cancer cells, and its deletion in the pancreas leads to decreased tumor formation in genetically engineered mouse models of pancreatic cancer. However, the impact of NFκB signaling in tumor stroma on pancreatic cancer growth is still unclear. Preliminary results from our lab suggest that NFκB signaling in pancreatic cancer stroma is pro-tumorigenic and protects cancer cells from T cell-dependent tumor elimination. Our in vitro studies and analysis of TCGA human pancreatic cancer data suggest that CCL5 or RANTES may be one of the key cytokines that mediates this pro- tumorigenic effect. In the current grant, we propose to corroborate our novel findings and the overall aim of this study is to investigate the mechanisms by which NFκB in tumor stroma protects cancer cells from immune- mediated cell death. We are confident that the successful completion of this study could provide new insights into the role played by stromal NFκB/CCL5 in pancreatic cancer growth and metastases. These findings could be used to enhance the efficacy of immune checkpoint therapy which, so far, has had limited success against pancreatic cancer.

Public health relevance public domain (NIH RePORTER)

While previous research primarily focused on the properties of the cancer cell, in recent years, there has been an increasing interest in understanding the role of the tumor stroma in supporting cancer growth. It has become clear that to develop effective strategies against pancreatic cancer, tumor stroma needs to be addressed. In this regard, our preliminary data suggest that NFκB signaling in pancreatic cancer stroma is pro-tumorigenic and promotes tumor growth by creating an immunosuppressive environment. In the current grant application, we will decipher how stromal NFκB modulates pancreatic cancer growth. Successful completion of these studies will lead to discovery of novel strategies to modulate tumor microenvironment for therapeutic purposes.