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

Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation

Procopio, Maria-Giuseppina
•
Laszlo, Csaba
•
Al Labban, Dania
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2015
Nature Cell Biology

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.

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Type
research article
DOI
10.1038/ncb3228
Web of Science ID

WOS:000361113700013

PubMed ID

26302407

Author(s)
Procopio, Maria-Giuseppina
Laszlo, Csaba
Al Labban, Dania
Kim, Dong Eun
Bordignon, Pino
Jo, Seung-Hee
Goruppi, Sandro
Menietti, Elena
Ostano, Paola
Ala, Ugo
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Date Issued

2015

Publisher

Nature Publishing Group

Published in
Nature Cell Biology
Volume

17

Issue

9

Start page

1193

End page

1204

Editorial or Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
UPBRI  
Available on Infoscience
September 7, 2015
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/117640
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