title: Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation.
abstract: 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.
authors: Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland.
authors: Maria-Giuseppina
authors: MG
authors: Procopio
authors: Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland.
authors: Csaba
authors: C
authors: Laszlo
authors: Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland.
authors: Dania
authors: D
authors: Al Labban
authors: Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland.
authors: Dong Eun
authors: DE
authors: Kim
authors: Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland.
authors: Pino
authors: P
authors: Bordignon
authors: Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
authors: Seung-Hee
authors: SH
authors: Jo
authors: Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
authors: Sandro
authors: S
authors: Goruppi
authors: Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland.
authors: Elena
authors: E
authors: Menietti
authors: Cancer Genomics Laboratory, Edo and Elvo Tempia Valenta Foundation, Biella 13900, Italy.
authors: Paola
authors: P
authors: Ostano
authors: Department of Molecular Biotechnology and Life Sciences, University of Turin, Turin 10126, Italy.
authors: Ugo
authors: U
authors: Ala
authors: Department of Molecular Biotechnology and Life Sciences, University of Turin, Turin 10126, Italy.
authors: Paolo
authors: P
authors: Provero
authors: Department of Dermatology, Zürich University, Zürich CH-8091, Switzerland.
authors: Wolfram
authors: W
authors: Hoetzenecker
authors: Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors: Victor
authors: V
authors: Neel
authors: Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne CH-1015, Switzerland.
authors: Witold W
authors: WW
authors: Kilarski
authors: Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne CH-1015, Switzerland.
authors: Melody A
authors: MA
authors: Swartz
authors: Swiss Institute of Experimental Cancer Research (ISREC), Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne CH-1015, Switzerland.
authors: Cathrin
authors: C
authors: Brisken
authors: Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland.|Department of Medicine, Section of Dermatology, University Hospital CHUV, Lausanne CH-1011, Switzerland.
authors: Karine
authors: K
authors: Lefort
authors: Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland.|Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
authors: G Paolo
authors: GP
authors: Dotto
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D015536:Down-Regulation; D005347:Fibroblasts / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497570:RBPJ protein, human; D017468:Receptors, Fibroblast Growth Factor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53