Biology subjects

BERNARD-PIERROT, I.

Publications and source records attributed to BERNARD-PIERROT, I..

3 recordsLinked to original sources

bioRxiv2022

Epigenomic mapping identifies a super-enhancer repertoire that regulates cell identity in bladder cancers through distinct transcription factor networks

Muscle-invasive bladder cancer (BLCA) is an aggressive disease. Consensus BLCA transcriptomic subtypes have been proposed, with two major Luminal and Basal subgroups, presenting distinct molecular and clinical characteristics. However, how these distinct subtypes are regulated remains unclear. We hypothesized that epigenetic activation of distinct super-enhancers could drive the transcriptional programs of BLCA subtypes. Through integrated RNA-sequencing and epigenomic profiling of histone marks in primary tumours, cancer cell lines, and normal human urothelia, we established the first integrated epigenetic map of BLCA and demonstrated the link between subtype and epigenetic control. We identified the repertoire of activated super-enhancers and highlighted Basal, Luminal and Normal-associated SEs. We revealed the super-enhancer-regulated networks of candidate master transcription factors for Luminal and Basal subgroups including FOXA1 and ZBED2 respectively. FOXA1 CRISPR-Cas9 mutation triggered a shift from Luminal to Basal phenotype, confirming its role in Luminal identity regulation and induced ZBED2 overexpression. In parallel, we showed that both FOXA1 and ZBED2 play concordant roles in preventing inflammatory response in cancer cells through STAT2 inhibition. Our study furthers the understanding of epigenetic regulation of muscle-invasive BLCA and identifies a co-regulated network of super-enhancers and associated transcription factors providing potential targets for the treatment of this aggressive disease.

cancer biology↗

bioRxiv2021

FGFR3 activating mutations induce luminal-like papillary bladder tumor formation and favor a male gender bias.

BackgroundFGFR3 mutations are among the most frequent genetic alterations in bladder cancer and are enriched in the luminal papillary subtype of muscle-invasive tumors (MIBC) and luminal-like classes 1 and 3 of non-MIBC. To study their oncogenic properties in vivo, we developed here a genetically engineered mouse (GEM) model expressing the most frequent FGFR3 mutation, FGFR3-S249C, in urothelial cells. MethodsBladder tumorigenesis was monitored in FGFR3-S249C mice. FGFR3 expression was assessed by RT-qPCR in the transgenic mice urothelium and in various human epithelia. Transcriptomic data were obtained from mouse bladder tumors and crossspecies comparisons were performed. Sex bias in FGFR3-mutated tumors was evaluated in our GEM model and in the TCGA and UROMOL cohorts of patients including 408 MIBC and 419 NMIBC, respectively. The association of androgen receptor (AR) activity, based on the expression of its target genes, with FGFR3 mutations was examined in these two cohorts. Binding of AR to its response element and AR phosphorylation in FGFR3-dependent cell lines were evaluated. ResultsFGFR3-S249C expression in the urothelium of mice induced spontaneous low-grade papillary bladder tumors resembling the human counterpart at the histological and transcriptomic levels. Mutant-FGFR3 expression levels impacted tumor formation incidence in mice and mutant-FGFR3-driven human tumors were restricted to epithelia presenting high normal expression levels of FGFR3. The known bladder cancer male gender bias, also found in our model, was even higher in human FGFR3-mutated compared to wild-type tumors and associated with a higher AR regulon activity considering gender adjustment. AR phosphorylation and regulon activity were modulated by FGFR3 in FGFR3-dependent models. ConclusionsMutant-FGFR3 is an oncogene per se, inducing bladder tumorigenesis. Patients with early stage bladder lesions could thus potentially benefit from FGFR3 targeting. Our results also reinforce the interest in elucidating the role of AR in bladder carcinogenesis, specifically in FGFR3-mutated driven tumors. Finally, our results suggest FGFR3 expression level in epithelium as a determinant for the FGFR3-driven tumors tissue specificity.

cancer biology↗

bioRxiv2019

PPARG is a tumor suppressor in basal bladder tumors offering new potential therapeutic opportunities.

PPAR{gamma} activation is a critical event in luminal muscle-invasive bladder cancer (MIBC) tumorigenesis, favoring both tumor cell growth and microenvironment modulation toward tumor immune escape. Conversely, the down-regulation of PPAR{gamma} activity in basal MIBC suggests tumor suppressive effects in this subgroup. Here, we report genetic, epigenetic and functional evidence to support the tumor suppressor role for PPAR{gamma} in basal bladder tumors. We identified hemizygous deletions, DNA hyper-methylation and loss-of-function mutations of PPAR{gamma} in basal MIBC, associated with PPAR{gamma} under-expression and its decreased activity. Re-expression of PPAR{gamma} in basal tumor cells resulted in the activation of PPAR{gamma} -dependent transcription program that modulated fatty acid metabolism and cell differentiation and decreased cell growth, which could partly rely on EGFR down-regulation. Structure-function studies of two PPAR{gamma} mutant revealed a destabilization of a region important for coactivator recruitment and should help develop potent molecules to activate PPAR{gamma} as a therapeutic strategy for basal MIBC. The identification of this subtype-dependent dual role of PPAR{gamma} in MIBC strengthens the critical role of PPAR{gamma} in bladder tumorigenesis and reinforces the interest in stratified medicine based on tumor molecular subtyping. One sentence summaryGenetic, epigenetic and functional evidence of a tumor suppressor role for PPAR{gamma} in basal bladder tumors offer new therapeutic opportunities for this subgroup.

cancer biology↗