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

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

Tel Aviv University, Technion - Israel Institute of Technology

Research output: Contribution to journal › Article › peer-review

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 language	English
Pages (from-to)	564-578
Number of pages	15
Journal	Cell
Volume	158
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2014.05.045
State	Published - 31 Jul 2014

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SDG 3 Good Health and Well-being

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General Biochemistry,Genetics and Molecular Biology

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@article{f9552a41324f4d9fbba3f380e0be1745,

title = "The reprogramming of tumor stroma by HSF1 is a potent enabler of malignancy",

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.",

author = "Ruth Scherz-Shouval and Sandro Santagata and Mendillo, \{Marc L\} and Sholl, \{Lynette M\} and Irit Ben-Aharon and Beck, \{Andrew H\} and Dora Dias-Santagata and Martina Koeva and Stemmer, \{Salomon M\} and Luke Whitesell and Susan Lindquist",

note = "Funding Information: We thank I. Barrasa, G. Bell, S. Gupta, and T. DiCesare for bioinformatic analysis and graphical assistance. We thank M. Duquette and A. Topolszky (WIBR), K. Lynch (MGH), and A. Tuvar (Rabin Medical Center) for technical assistance. We thank C.K. Dai for cloning Bi-Tet- Hsf1 and R. Jaenisch and Y. Freyzon for construction of Bi-Tet- Hsf1 transgenic mice. We thank K. Polyak, P. Gupta, D. Pincus, L. Clayton, and members of the S.L. lab for helpful discussions and comments. We thank R. Weinberg for the gift of cell lines and for helpful discussions. R.S.-S. was supported by the Human Frontiers Science Program, the Fulbright Program, and the Israel National Postdoctoral Award Program for Women in Science. S.S. is supported by the Jared Branfman Sunflowers for Life Fund, the V Foundation, and by NIH grant K08 NS064168. M.L.M. was supported by the National Cancer Institute of the NIH under Award Number K99CA175293. L.W. was supported by the Komen Foundation, Grant KG110450, and by the J\&J COSAT focused funding program. S.L. is an investigator of the Howard Hughes Medical Institute. Support for this study was also provided by the Alexander and Margaret Stewart Trust and the Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund. D.D.-S. is a consultant for Bioreference Labs, submitted a patent application (pending) for the SNaPshot methods described here, has licensed SNaPshot technology, and receives royalties from Bioreference Labs.",

year = "2014",

month = jul,

day = "31",

doi = "10.1016/j.cell.2014.05.045",

language = "الإنجليزيّة",

volume = "158",

pages = "564--578",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "3",

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T1 - The reprogramming of tumor stroma by HSF1 is a potent enabler of malignancy

AU - Scherz-Shouval, Ruth

AU - Santagata, Sandro

AU - Mendillo, Marc L

AU - Sholl, Lynette M

AU - Ben-Aharon, Irit

AU - Beck, Andrew H

AU - Dias-Santagata, Dora

AU - Koeva, Martina

AU - Stemmer, Salomon M

AU - Whitesell, Luke

AU - Lindquist, Susan

N1 - Funding Information: We thank I. Barrasa, G. Bell, S. Gupta, and T. DiCesare for bioinformatic analysis and graphical assistance. We thank M. Duquette and A. Topolszky (WIBR), K. Lynch (MGH), and A. Tuvar (Rabin Medical Center) for technical assistance. We thank C.K. Dai for cloning Bi-Tet- Hsf1 and R. Jaenisch and Y. Freyzon for construction of Bi-Tet- Hsf1 transgenic mice. We thank K. Polyak, P. Gupta, D. Pincus, L. Clayton, and members of the S.L. lab for helpful discussions and comments. We thank R. Weinberg for the gift of cell lines and for helpful discussions. R.S.-S. was supported by the Human Frontiers Science Program, the Fulbright Program, and the Israel National Postdoctoral Award Program for Women in Science. S.S. is supported by the Jared Branfman Sunflowers for Life Fund, the V Foundation, and by NIH grant K08 NS064168. M.L.M. was supported by the National Cancer Institute of the NIH under Award Number K99CA175293. L.W. was supported by the Komen Foundation, Grant KG110450, and by the J&J COSAT focused funding program. S.L. is an investigator of the Howard Hughes Medical Institute. Support for this study was also provided by the Alexander and Margaret Stewart Trust and the Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund. D.D.-S. is a consultant for Bioreference Labs, submitted a patent application (pending) for the SNaPshot methods described here, has licensed SNaPshot technology, and receives royalties from Bioreference Labs.

PY - 2014/7/31

Y1 - 2014/7/31

N2 - 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.

AB - 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.

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U2 - 10.1016/j.cell.2014.05.045

DO - 10.1016/j.cell.2014.05.045

M3 - مقالة

C2 - 25083868

SN - 0092-8674

VL - 158

SP - 564

EP - 578

JO - Cell

JF - Cell

IS - 3

ER -

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

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