A multistep process of cancer associated fibroblasts determination under CSL-p53 control

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Demande d'une copie
ID Serval
serval:BIB_E5E65B1E7B70
Type
Thèse: thèse de doctorat.
Collection
Publications
Titre
A multistep process of cancer associated fibroblasts determination under CSL-p53 control
Auteur(s)
Procopio M. G.
Directeur(s)
DOTTO G.
Détails de l'institution
Université de Lausanne, Faculté de biologie et médecine
Adresse
Faculté de biologie et de médecineUniversité de LausanneCH-1015 LausanneSUISSE
Statut éditorial
Acceptée
Date de publication
2015
Langue
anglais
Nombre de pages
72
Résumé
Stromal fibroblast senescence has been linked to the aging-associated increase of tumors. However, in epithelial cancer, density and proliferation of cancer associated fibroblasts (CAF) are frequently increased, rather than decreased. We previously showed that genetic deletion or down-modulation of the canonical Notch effector CSL/RBP-JK in dermal fibroblasts is sufficient for CAF activation with consequent development of keratinocyte-derived tumors. We show here that CSL silencing induces senescence of primary fibroblasts from dermis, oral mucosa, breast and lung. CSL functions in these cells as direct repressor of multiple senescence- and CAF-effector genes. It also physically interacts with p53, repressing its activity. CSL is down-modulated in stromal fibroblasts of premalignant skin actinic keratosis lesions and squamous cell carcinomas (SCC), while p53 gene expression and function is down-modulated only in the latter, with paracrine influences of incipient cancer cells as a likely culprit. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances CAF effector gene expression and promotes stromal and cancer cell expansion. The findings support a CAF activation/stromal co-evolution model under convergent CSL/p53 control of likely clinical relevance.
Création de la notice
08/10/2015 11:41
Dernière modification de la notice
20/08/2019 16:09
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