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

doi:10.1016/j.cell.2014.05.045

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

Cell. 2014 Jul 31;158(3):564-78. doi: 10.1016/j.cell.2014.05.045.

Authors

Affiliations

¹ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
² Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Department of Cancer Biology, Dana Farber Cancer Center, Boston, MA 02215, USA.
³ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
⁴ Institute of Oncology, Davidoff Center, Rabin Medical Center, Petach Tikva 49100, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel.
⁵ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
⁶ Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02215, USA.
⁷ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁸ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Electronic address: whitesell@wi.mit.edu.
⁹ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Cambridge, MA 02142, USA. Electronic address: lindquist_admin@wi.mit.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Breast Neoplasms / metabolism*
Chemokine CXCL12 / metabolism
DNA-Binding Proteins / metabolism*
Fibroblasts / metabolism
Heat Shock Transcription Factors
Heterografts
Humans
Lung Neoplasms / metabolism*
MCF-7 Cells
Mice
Mice, Inbred NOD
Mice, SCID
Neoplasm Transplantation
Transcription Factors / metabolism*
Transforming Growth Factor beta / metabolism

Substances

Chemokine CXCL12
DNA-Binding Proteins
HSF1 protein, human
Heat Shock Transcription Factors
Transcription Factors
Transforming Growth Factor beta

Associated data

GEO/GSE56252

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding