Cell Autonomous and Non-Cell-Autonomous Activities of Heat Shock Factor 1 in Cancer

For tumors to expand, invade and metastasize, the recruitment and reprogramming of non-malignant stromal cells is required. Yet surprisingly little is known about the factors that drive the transcriptional reprogramming of stromal cells within tumors. Our work shows that Heat-shock Factor 1 (HSF1), an evolutionarily conserved transcription master regulator, plays a crucial role in this process. Across a broad range of human cancers, HSF1 is activated not only in the malignant cells themselves, but in cancer-associated fibroblasts (CAFs). HSF1 drives a transcriptional program in CAFs that complements, yet is completely different from, the program it drives in adjacent cancer cells. Recently we have shown that this CAF program is uniquely structured to support the malignant potential of cancer cells in a non-cell-autonomous way. In early stage breast and lung cancer, high stromal HSF1 activation is strongly associated with poor patient outcome. Here we further explore the HSF1-dependent cross talk between cancer and stroma. We dissect the mechanism of stromal HSF1 activation, identify key components of the HSF1-dependent stromal transcriptional program and highlight the prognostic implications of cell-autonomous and non-cell-autonomous activation of HSF1.