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Cited by 386Heat shock proteins researchTGF-β signaling in diseasesCancer Cells and Metastasis

The Reprogramming of Tumor Stroma by HSF1 Is a Potent Enabler of Malignancy

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Scherz-Shouval, Ruth, Santagata, Sandro, Mendillo, Marc L., Sholl, Lynette M., Ben-Aharon, Irit, Beck, Andrew H., Dias-Santagata, Dora, Koeva, Martina +3 more·2014·Cell
DOI 10.1016/j.cell.2014.05.045PMC PMC4249939
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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.

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  • HSF1 is required for the generation of CAFs.

    “Heat shock factor 1 (HSF1), which responds in part to protein misfolding, is required for the generation of CAFs67,68.”

    From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [67]

    The Results sections on stromal transcriptional programs and TGFβ/SDF1 signaling show that HSF1 helps fibroblasts acquire tumor-supporting properties associated with CAFs. They do not establish that HSF1 is required for CAFs to be generated; the paper also describes stromal fibroblasts in tumors formed with Hsf1-null fibroblasts. Page numbers are unavailable in our copy. (LLM, conf=0.86)

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References 51 · Cited by 386

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  1. Beck AH Espinosa I Gilks CB van de Rijn M West RB 2008 The fibromatosis signature defines a robust stromal response in breast carcinoma Lab Invest 88 591 601 18414401 PMC4847137
  2. Bissell MJ Hines WC 2011 Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression Nat Med 17 320 329 21383745 PMC3569482
  3. Chang HY Sneddon JB Alizadeh AA Sood R West RB Montgomery K Chi JT van de Rijn M Botstein D Brown PO 2004 Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds PLoS Biol 2 E7 14737219 PMC314300
  4. Dai C Santagata S Tang Z Shi J Cao J Kwon H Bronson RT Whitesell L Lindquist S 2012 Loss of tumor suppressor NF1 activates HSF1 to promote carcinogenesis J Clin Invest 122 3742 3754 22945628 PMC3461912
  5. Dai C Whitesell L Rogers AB Lindquist S 2007 Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis Cell 130 1005 1018 17889646 PMC2586609
  6. Dias-Santagata D Akhavanfard S David SS Vernovsky K Kuhlmann G Boisvert SL Stubbs H McDermott U Settleman J Kwak EL 2010 Rapid targeted mutational analysis of human tumours: a clinical platform to guide personalized cancer medicine Embo Mol Med 2 146 158 20432502 PMC3377316
  7. Dituri F Mazzocca A Peidro FJ Papappicco P Fabregat I De Santis F Paradiso A Sabba C Giannelli G 2013 Differential Inhibition of the TGF-beta Signaling Pathway in HCC Cells Using the Small Molecule Inhibitor LY2157299 and the D10 Monoclonal Antibody against TGF-beta Receptor Type II Plos One 8 e67109 23826206 PMC3694933
  8. Erez N Truitt M Olson P Arron ST Hanahan D 2010 Cancer-Associated Fibroblasts Are Activated in Incipient Neoplasia to Orchestrate Tumor-Promoting Inflammation in an NF-kappaB-Dependent Manner Cancer Cell 17 135 147 20138012
  9. Fang F Chang R Yang L 2012 Heat shock factor 1 promotes invasion and metastasis of hepatocellular carcinoma in vitro and in vivo Cancer 118 1782 1794 22009757
  10. Finak G Bertos N Pepin F Sadekova S Souleimanova M Zhao H Chen H Omeroglu G Meterissian S Omeroglu A 2008 Stromal gene expression predicts clinical outcome in breast cancer Nat Med 14 518 527 18438415
  11. Goldstraw P Crowley J Chansky K Giroux DJ Groome PA Rami-Porta R Postmus PE Rusch V Sobin L 2007 The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours J Thorac Oncol 2 706 714 17762336
  12. Hanahan D Weinberg RA 2011 Hallmarks of cancer: the next generation Cell 144 646 674 21376230
  13. Henderson B Kaiser F 2013 Do reciprocal interactions between cell stress proteins and cytokines create a new intra-/extra-cellular signalling nexus? Cell Stress Chaperones PMC3789882 23884786
  14. Jin X Moskophidis D Mivechi NF 2011 Heat shock transcription factor 1 is a key determinant of HCC development by regulating hepatic steatosis and metabolic syndrome Cell Metab 14 91 103 21723507 PMC3214631
  15. Kalluri R Zeisberg M 2006 Fibroblasts in cancer Nat Rev Cancer 6 392 401 16572188
  16. Karnoub AE Dash AB Vo AP Sullivan A Brooks MW Bell GW Richardson AL Polyak K Tubo R Weinberg RA 2007 Mesenchymal stem cells within tumour stroma promote breast cancer metastasis Nature 449 557 563 17914389
  17. Kojima Y Acar A Eaton EN Mellody KT Scheel C Ben-Porath I Onder TT Wang ZC Richardson AL Weinberg RA 2010 Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts Proc Natl Acad Sci U S A 107 20009 20014 21041659 PMC2993333
  18. Lee TI Johnstone SE Young RA 2006 Chromatin immunoprecipitation and microarray-based analysis of protein location Nat Protoc 1 729 748 17406303 PMC3004291
  19. Luo J Solimini NL Elledge SJ 2009 Principles of cancer therapy: oncogene and non-oncogene addiction Cell 136 823 837 19269363 PMC2894612
  20. Maity TK Henry MM Tulapurkar ME Shah NG Hasday JD Singh IS 2011 Distinct, gene-specific effect of heat shock on heat shock factor-1 recruitment and gene expression of CXC chemokine genes Cytokine 54 61 67 21266308 PMC3048923
  21. Mendillo ML Santagata S Koeva M Bell GW Hu R Tamimi RM Fraenkel E Ince TA Whitesell L Lindquist S 2012 HSF1 drives a transcriptional program distinct from heat shock to support highly malignant human cancers Cell 150 549 562 22863008 PMC3438889
  22. Meng L Gabai VL Sherman MY 2010 Heat-shock transcription factor HSF1 has a critical role in human epidermal growth factor receptor-2-induced cellular transformation and tumorigenesis Oncogene 29 5204 5213 20622894 PMC2940982
  23. Morimoto RI 2008 Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging Genes Dev 22 1427 1438 18519635 PMC2732416
  24. Moskovits N Kalinkovich A Bar J Lapidot T Oren M 2006 p53 Attenuates cancer cell migration and invasion through repression of SDF-1/CXCL12 expression in stromal fibroblasts Cancer Res 66 10671 10676 17108103
  25. Olumi AF Grossfeld GD Hayward SW Carroll PR Tlsty TD Cunha GR 1999 Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium Cancer Res 59 5002 5011 10519415 PMC3300837
  26. Pickup M Novitskiy S Moses HL 2013 The roles of TGFbeta in the tumour microenvironment Nat Rev Cancer 13 788 799 24132110 PMC4025940
  27. Pillai RN Ramalingam SS 2014 Advances in the diagnosis and treatment of non-small cell lung cancer Mol Cancer Ther 13 557 564 24516099
  28. Place AE Jin Huh S Polyak K 2011 The microenvironment in breast cancer progression: biology and implications for treatment Breast Cancer Res 13 227 22078026 PMC3326543
  29. Prahlad V Cornelius T Morimoto RI 2008 Regulation of the cellular heat shock response in Caenorhabditis elegans by thermosensory neurons Science 320 811 814 18467592 PMC3429343
  30. Qiu W Hu M Sridhar A Opeskin K Fox S Shipitsin M Trivett M Thompson ER Ramakrishna M Gorringe KL 2008 No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas Nat Genet 40 650 655 18408720 PMC3745022
  31. Quante M Tu SP Tomita H Gonda T Wang SS Takashi S Baik GH Shibata W Diprete B Betz KS 2011 Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth Cancer Cell 19 257 272 21316604 PMC3060401
  32. Sakurai H Enoki Y 2010 Novel aspects of heat shock factors: DNA recognition, chromatin modulation and gene expression FEBS J 277 4140 4149 20945530
  33. Santagata S Hu R Lin NU Mendillo ML Collins LC Hankinson SE Schnitt SJ Whitesell L Tamimi RM Lindquist S 2011 High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer Proc Natl Acad Sci U S A 108 18378 18383 22042860 PMC3215027
  34. Santagata S Mendillo ML Tang YC Subramanian A Perley CC Roche SP Wong B Narayan R Kwon H Koeva M 2013 Tight coordination of protein translation and HSF1 activation supports the anabolic malignant state Science 341 1238303 23869022 PMC3959726
  35. Santagata S Xu YM Wijeratne EM Kontnik R Rooney C Perley CC Kwon H Clardy J Kesari S Whitesell L 2012 Using the heat-shock response to discover anticancer compounds that target protein homeostasis Acs Chem Biol 7 340 349 22050377 PMC3291478
  36. Sasaki H Sato T Yamauchi N Okamoto T Kobayashi D Iyama S Kato J Matsunaga T Takimoto R Takayama T 2002 Induction of heat shock protein 47 synthesis by TGF-beta and IL-1 beta via enhancement of the heat shock element binding activity of heat shock transcription factor 1 J Immunol 168 5178 5183 11994473
  37. Saturno G Valenti M De Haven Brandon A Thomas GV Eccles S Clarke PA Workman P 2013 Combining Trail with PI3 Kinase or HSP90 inhibitors enhances apoptosis in colorectal cancer cells via suppression of survival signaling Oncotarget 4 1185 1198 23852390 PMC3787150
  38. Scott KL Nogueira C Heffernan TP van Doorn R Dhakal S Hanna JA Min C Jaskelioff M Xiao Y Wu CJ 2011 Proinvasion metastasis drivers in early-stage melanoma are oncogenes Cancer Cell 20 92 103 21741599 PMC3176328
  39. Shamovsky I Nudler E 2008 New insights into the mechanism of heat shock response activation Cell Mol Life Sci 65 855 861 18239856 PMC11131843
  40. Sholl LM Barletta JA Yeap BY Chirieac LR Hornick JL 2010 Sox2 protein expression is an independent poor prognostic indicator in stage I lung adenocarcinoma Am J Surg Pathol 34 1193 1198 20631605 PMC2923819
  41. Siegel PM Massague J 2003 Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer Nat Rev Cancer 3 807 821 14557817
  42. Trimboli AJ Cantemir-Stone CZ Li F Wallace JA Merchant A Creasap N Thompson JC Caserta E Wang H Chong JL 2009 Pten in stromal fibroblasts suppresses mammary epithelial tumours Nature 461 1084 1091 19847259 PMC2767301
  43. Whitesell L Lindquist S 2009 Inhibiting the transcription factor HSF1 as an anticancer strategy Expert Opin Ther Tar 13 469 478 19335068

Authors
Scherz-Shouval, R., Santagata, S., Mendillo, M. L., Sholl, L. M., Ben-Aharon, I., Beck, A. H., Dias-Santagata, D., Koeva, M., Stemmer, S. M., Whitesell, L., & Lindquist, S.
Affiliations
  • Brigham and Women's Hospital (US)
  • Whitehead Institute for Biomedical Research (US)
  • Beth Israel Deaconess Medical Center (US)
  • Harvard University (US)
  • Tel Aviv University (IL)
  • Howard Hughes Medical Institute (US)
Corresponding author
  • Whitesell, Luke
  • Lindquist, Susan
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2014-07
Volume
158
Issue
3
Pages
564-578
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2014.05.045
PMC
PMC4249939
OpenAlex
W2079488858
Cited by
386
References
51
Citations by year
2026: 11 · 2025: 22 · 2024: 47 · 2023: 28 · 2022: 29 · 2021: 41 · 2020: 44 · 2019: 40 · 2018: 24 · 2017: 29 · 2016: 35 · 2015: 28 · 2014: 8
FWCI
13.68
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
  • PMC
Funders
  • Howard Hughes Medical Institute
  • National Cancer Institute (K99CA175293, P30CA014051)
  • National Institute of Neurological Disorders and Stroke (K08NS064168)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
heat shock factor 1, cancer-associated fibroblasts, tumor microenvironment, stromal reprogramming, TGF-beta signaling, breast cancer, lung cancer, transcriptional reprogramming, patient outcomes
MeSH terms
Heat Shock Transcription Factors, Animals, Breast Neoplasms, DNA-Binding Proteins, Fibroblasts, Humans, Lung Neoplasms, Neoplasm Transplantation, Transcription Factors, Transforming Growth Factor beta, Mice, SCID, Mice, Inbred NOD, Mice, Chemokine CXCL12, MCF-7 Cells, Heterografts

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