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PMID: 25083868 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Cell ·Vol. 158 ·No. 3 ·2014-07-31 ·Pages 564-78

Scherz-Shouval R, Santagata S, Mendillo ML, Sholl LM, Ben-Aharon I, Beck AH, Dias-Santagata D, Koeva M, Stemmer SM, Whitesell L, Lindquist S

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.

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
Chemicals
Chemokine CXCL12 DNA-Binding Proteins HSF1 protein, human Heat Shock Transcription Factors Transcription Factors Transforming Growth Factor beta
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Scherz-Shouval Ruth
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Santagata Sandro
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.
Mendillo Marc L
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Sholl Lynette M
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Ben-Aharon Irit
Institute of Oncology, Davidoff Center, Rabin Medical Center, Petach Tikva 49100, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel.
Beck Andrew H
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Dias-Santagata Dora
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02215, USA.
Koeva Martina
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Stemmer Salomon M
Institute of Oncology, Davidoff Center, Rabin Medical Center, Petach Tikva 49100, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel.
Whitesell Luke
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Electronic address: [email protected].
Lindquist Susan
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: [email protected].
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2014.05.045
Email
[email protected]
[email protected]
Published
2014-07-31
Pages
564-78
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC4249939
Subset
IM
Grants
NINDS NIH HHS · K08 NS064168 · United States
Howard Hughes Medical Institute · United States
NCI NIH HHS · P30 CA014051 · United States
NCI NIH HHS · K99 CA175293 · United States
NCI NIH HHS · K99CA175293 · United States
Databases
GEO
GSE56252
Corrections
CommentIn
PMID: 25118604
External Links
PubMed source DOI: 10.1016/j.cell.2014.05.045 PMC Full Text View journal details
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