The reprogramming of tumor stroma by HSF1 is a potent enabler of malignancy

Ruth Scherz-Shouval, Sandro Santagata, Marc L. Mendillo, Lynette M. Sholl, Irit Ben-Aharon, Andrew H. Beck, Dora Dias-Santagata, Martina Koeva, Salomon M. Stemmer, Luke Whitesell*, Susan Lindquist

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

181 Scopus citations

Abstract

Stromal cells within the tumor microenvironment are essential for tumor progression and metastasis. Surprisingly little is known about the factors that drive the transcriptional reprogramming of stromal cells within tumors. We report that the transcriptional regulator heat shock factor 1 (HSF1) is frequently activated in cancer-associated fibroblasts (CAFs), where it is a potent enabler of malignancy. HSF1 drives a transcriptional program in CAFs that complements, yet is completely different from, the program it drives in adjacent cancer cells. This CAF program is uniquely structured to support malignancy in a non-cell-autonomous way. Two central stromal signaling molecules - TGF-β and SDF1 - play a critical role. In early-stage breast and lung cancer, high stromal HSF1 activation is strongly associated with poor patient outcome. Thus, tumors co-opt the ancient survival functions of HSF1 to orchestrate malignancy in both cell-autonomous and non-cell-autonomous ways, with far-reaching therapeutic implications.

Original languageEnglish (US)
Pages (from-to)564-578
Number of pages15
JournalCell
Volume158
Issue number3
DOIs
StatePublished - Jul 31 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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