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.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Scherz-Shouval
authors.affiliation: 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.
authors.forename: Sandro
authors.initials: S
authors.lastname: Santagata
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Marc L
authors.initials: ML
authors.lastname: Mendillo
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Sholl
authors.affiliation: Institute of Oncology, Davidoff Center, Rabin Medical Center, Petach Tikva 49100, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel.
authors.forename: Irit
authors.initials: I
authors.lastname: Ben-Aharon
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Beck
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Dora
authors.initials: D
authors.lastname: Dias-Santagata
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Martina
authors.initials: M
authors.lastname: Koeva
authors.affiliation: Institute of Oncology, Davidoff Center, Rabin Medical Center, Petach Tikva 49100, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel.
authors.forename: Salomon M
authors.initials: SM
authors.lastname: Stemmer
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Electronic address: whitesell@wi.mit.edu.
authors.forename: Luke
authors.initials: L
authors.lastname: Whitesell
authors.affiliation: 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.
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D054377:Chemokine CXCL12 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta
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