Identification of a key oncogenic role of p63 in altered-FGFR3 tumors through inference of bladder cancer gene regulatory network and functional validations - Centre de recherche des Cordeliers
Pré-Publication, Document De Travail Année : 2023

Identification of a key oncogenic role of p63 in altered-FGFR3 tumors through inference of bladder cancer gene regulatory network and functional validations

Aura Ileana Moreno Vega
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Florent Dufour
Claire Beraud
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Myriam Lasalle
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Elodie Chapeaublanc
Philipe Lluel
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Lars Dyrskjøt
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François Radvanyi

Résumé

The alteration of the receptor tyrosine kinase FGFR3 through activating mutations or translocations is one of the most common genetic events in bladder cancer (BLCA). Despite the demonstration of the oncogenic potential of such alterations, the gene regulatory network of an altered-FGFR3 in bladder cancer remains poorly characterized. We combined here a bioinformatic reverse-engineering inference approach together with in vitro and in vivo FGFR3-perturbation experiments to determine a BLCA regulatory network of transcription factors and co-factors (TFs/coTFs) that are driven by an altered-FGFR3 and critical for its oncogenic activity. Amongst them, we identified p63 in both non-muscle (NMIBC) and muscle invasive bladder cancers (MIBC) and further demonstrated that it mediates tumor growth, cell proliferation and migration of FGFR3-dependent bladder cancer cells. In Ta NMIBC, we observed both higher p63 activity and increased tendency of recurrence in tumors harboring a mutated-FGFR3 as compared to tumors with the wild-type receptor, suggesting that p63 activation by FGFR3 could favor recurrence. Our results elucidate an unexpected oncogenic key role of p63 in luminal papillary tumors bearing FGFR3 mutations and provide a global BLCA specific FGFR3-induced gene regulatory network that should allow a better understanding of FGFR3 induced oncogenic dependency that could have clinical applications.

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Dates et versions

hal-04687147 , version 1 (04-09-2024)

Identifiants

  • HAL Id : hal-04687147 , version 1

Citer

Aura Ileana Moreno Vega, Macarena Zambrano, Julia Puig, Florent Dufour, Clarice Groeneveld, et al.. Identification of a key oncogenic role of p63 in altered-FGFR3 tumors through inference of bladder cancer gene regulatory network and functional validations. 2023. ⟨hal-04687147⟩
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