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

Cell. 2014 Jul 31;158(3):564-78. doi: 10.1016/j.cell.2014.05.045.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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

Substances

  • Chemokine CXCL12
  • DNA-Binding Proteins
  • HSF1 protein, human
  • Heat Shock Transcription Factors
  • Transcription Factors
  • Transforming Growth Factor beta

Associated data

  • GEO/GSE56252