Abstract PR07: Mechanisms of stromal reprogramming mediated by heat shock factor 1

Abstract

Abstract For tumors to form, progress and metastasize, they must recruit and reprogram normal cells in their microenvironment into a pro-tumorigenic stroma. Yet little is known about the pathways leading to stromal reprogramming. We hypothesized that such reprogramming would not be mediated by classic oncogenes, since the stroma is relatively genetically stable. Instead we propose that cancer cells hijack normal cytoprotective stress responses, and subvert them to enable stromal reprogramming. We found that Heat-shock factor 1 (HSF1), master regulator of the heat-shock response, plays a crucial role in this process. Across a broad range of human cancers, HSF1 is activated in cancer-associated fibroblasts (CAFs). In early stage breast and lung cancer, high stromal HSF1 activation is strongly associated with poor patient outcome. In fibroblasts co-cultured with cancer cells, HSF1 drives a transcriptional program that supports cancer phenotypes. This program is profoundly different from the transcriptional program it drives in cancer cells or in heat-shocked cells. Here we characterize mechanisms leading to activation of this unique stromal program and describe the contribution of cancer cells to this process. We then explore the stromal HSF1 program in patients. We apply computational and experimental approaches to define independent cancer and stromal HSF1 signatures and highlight the prognostic value of these signatures in human breast cancer. Billions of years of evolution through changing environments led organisms to develop an arsenal of cytoprotective pathways to promote their survival under stressful conditions. Our work provides insights into the ways by which tumors co-opt these normal biological networks to support their survival in the stressful tumor microenvironment. This abstract is also presented as Poster B40. Citation Format: Ruth Scherz-Shouval, Marc L. Mendillo, Giorgio Gaglia, Irit Ben-Aharon, Andrew H. Beck, Luke Whitesell, Susan Lindquist. Mechanisms of stromal reprogramming mediated by heat shock factor 1. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr PR07.