Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation

Nat Cell Biol. 2015 Sep;17(9):1193-204. doi: 10.1038/ncb3228. Epub 2015 Aug 24.


Stromal fibroblast senescence has been linked to ageing-associated cancer risk. However, density and proliferation of cancer-associated fibroblasts (CAFs) are frequently increased. Loss or downmodulation of the Notch effector CSL (also known as RBP-Jκ) in dermal fibroblasts is sufficient for CAF activation and ensuing keratinocyte-derived tumours. We report that CSL silencing induces senescence of primary fibroblasts from dermis, oral mucosa, breast and lung. CSL functions in these cells as a direct repressor of multiple senescence- and CAF-effector genes. It also physically interacts with p53, repressing its activity. CSL is downmodulated in stromal fibroblasts of premalignant skin actinic keratosis lesions and squamous cell carcinomas, whereas p53 expression and function are downmodulated only in the latter, with paracrine FGF signalling as the probable culprit. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances expression of CAF effectors and promotes stromal and cancer cell expansion. The findings support a CAF activation-stromal co-evolution model under convergent CSL-p53 control.

Publication types

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

MeSH terms

  • Animals
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Cellular Senescence
  • Down-Regulation
  • Fibroblasts / physiology*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism*
  • Mice
  • Receptors, Fibroblast Growth Factor / metabolism
  • Signal Transduction
  • Skin Neoplasms / metabolism*
  • Skin Neoplasms / pathology
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*


  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • RBPJ protein, human
  • Receptors, Fibroblast Growth Factor
  • TP53 protein, human
  • Tumor Suppressor Protein p53