TY - JOUR
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 - Article
C2 - 25083868
AN - SCOPUS:84905369461
VL - 158
SP - 564
EP - 578
JO - Cell
JF - Cell
SN - 0092-8674
IS - 3
ER -
