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PMID: 26302407 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation.

Nature cell biology ·Vol. 17 ·No. 9 ·2015-09-00 ·Pages 1193-204

Procopio MG, Laszlo C, Al Labban D, Kim DE, Bordignon P, Jo SH, Goruppi S, Menietti E, Ostano P, Ala U, Provero P, Hoetzenecker W, Neel V, Kilarski WW, Swartz MA, Brisken C, Lefort K, Dotto GP

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.

MeSH Terms
Animals Carcinoma, Squamous Cell/metabolism,pathology Cell Line, Tumor Cellular Senescence Down-Regulation Fibroblasts/physiology Gene Expression Regulation, Neoplastic Humans Immunoglobulin J Recombination Signal Sequence-Binding Protein/genetics,metabolism Mice Receptors, Fibroblast Growth Factor/metabolism Signal Transduction Skin Neoplasms/metabolism,pathology Tumor Suppressor Protein p53/genetics,metabolism
Chemicals
Immunoglobulin J Recombination Signal Sequence-Binding Protein RBPJ protein, human Receptors, Fibroblast Growth Factor TP53 protein, human Tumor Suppressor Protein p53
Authors & Affiliations
18 authors, click to expand affiliations / ORCID
Procopio Maria-Giuseppina
Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland.
Laszlo Csaba
Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland.
Al Labban Dania
Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland.
Kim Dong Eun
Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland.
Bordignon Pino
Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland.
Jo Seung-Hee
Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
Goruppi Sandro
Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
Menietti Elena
Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland.
Ostano Paola
Cancer Genomics Laboratory, Edo and Elvo Tempia Valenta Foundation, Biella 13900, Italy.
Ala Ugo
Department of Molecular Biotechnology and Life Sciences, University of Turin, Turin 10126, Italy.
Provero Paolo
Department of Molecular Biotechnology and Life Sciences, University of Turin, Turin 10126, Italy.
Hoetzenecker Wolfram
Department of Dermatology, Zürich University, Zürich CH-8091, Switzerland.
Neel Victor
Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Kilarski Witold W
Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne CH-1015, Switzerland.
Swartz Melody A
Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne CH-1015, Switzerland.
Brisken Cathrin
Swiss Institute of Experimental Cancer Research (ISREC), Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne CH-1015, Switzerland.
Lefort Karine
Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland. | Department of Medicine, Section of Dermatology, University Hospital CHUV, Lausanne CH-1011, Switzerland.
Dotto G Paolo
Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland. | Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
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Article Info
Journal
Nature cell biology
Abbr.
Nat Cell Biol
ISSN
1476-4679
DOI
10.1038/ncb3228
Published
2015-09-00
Epub
2015-00-24
Pages
1193-204
Language
English
Region
England
NLM ID
100890575
PMCID
PMC4699446
Subset
IM
Grants
NIAMS NIH HHS · R01 AR039190 · United States
NIAMS NIH HHS · R01 AR064786 · United States
NIAMS NIH HHS · R01AR039190 · United States
NIAMS NIH HHS · R01AR064786 · United States
Corrections
ErratumIn
PMID: 26419803
External Links
PubMed source DOI: 10.1038/ncb3228 PMC Full Text View journal details
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