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To clarify the function of cyclin A2 in colon homeostasis and colorectal cancer (CRC), we generated mice deficient for cyclin A2 in colonic epithelial cells (CEC). Colons of those mice displayed architectural changes in the mucosa, and signs of inflammation as well as an increased proliferation of CEC associated with the appearance of low- and high-grade dysplasia. The main initial events triggering those alterations in cyclin A2 deficient CEC appear to be abnormal mitoses and DNA damage. Cyclin A2 deletion in CEC promoted the development of dysplasia and adenocarcinomas in the murine colitis-associated cancer model. We next explored the status of cyclin A2 expression in clinical CRC samples at the mRNA and protein level and found higher expression in tumors of stage I and II patients compared to those of stage III and IV. A meta-analysis of 11 transcriptome datasets comprising 2,239 primary CRC tumors displayed different CCNA2 (the mRNA coding for cyclin A2) expression levels among the CRC tumor subtypes with highest in CMS1 and lowest in CMS4. Moreover, high expression of CCNA2 was found to be a new independent prognosis factor for CRC tumors.

The association between pancreatic ductal adenocarcinoma (PDAC) location (head vs. Body/Tail (B/T)) and clinical outcome remains controversial. We collected clinicopathological and gene expression data from 249 resected PDAC samples from public data sets, and we compared data between 208 head and 41 B/T samples. The 2-year overall survival (OS) was better for the head than for the B/T PDACs (44 vs. 27%, p = 0.043), especially when comparing tumors with similar TNM classification (T3/4N0M0: 67% vs. 17%, p = 0.002) or from the same molecular class (squamous subtype: 31% vs. 0%, p &lt, 0.0001). Bailey&rsquo, s molecular subtypes were differentially distributed within the two groups, with the immunogenic subtype being underrepresented in the &ldquo, B/T&rdquo, group (p = 0.005). Uni- and multivariate analyses indicated that PDAC anatomic location was an independent prognostic factor. Finally, the supervised analysis identified 334 genes differentially expressed. Genes upregulated in the &ldquo, head&rdquo, group suggested lymphocyte activation and pancreas exocrine functions. Genes upregulated in the &ldquo, group were related to keratinocyte differentiation, in line with the enrichment for squamous phenotype. We identified a robust gene expression signature (GES) associated with B/T PDAC location, suggesting that head and B/T PDAC are different. This GES could serve as an indicator for differential therapeutic management based on PDAC location.

Many substrates of HSP90 are involved in signal transduction pathways and related to tumour progression. Inhibition of HSP90 has anti-tumoral effects. Identification of the R2TP, a new HSP90 co-chaperon, allowed the identification of a new set of HSP90 substrates. HSP90/R2TP is involved in the assembly of snoRNPs, telomerase RNP, the nuclear RNA polymerases and PIKKs, which play key functions in cellular proliferation and tumorigenesis. R2TP is formed of four proteins: RUVBL1, RUVBL2, PIH1D1 and RPAP3, some of which are overexpressed in hepatocellular and colorectal cancer. We thus hypothesize that the co-chaperone R2TP could be involved in colorectal carcinogenesis.To study the role of R2TP in intestinal homeostasis and carcinogenesis, we generated a conditional knock-out murine model for RPAP3. We showed that RPAP3 invalidation in whole organism or only in colon is lethal at embryonic stage. The invalidation of RPAP3 in adult intestine, using an inducible recombinase (RPAP3 fl; Villin>Cre-ERT2), leads to a drastic phenotype as soon as 8 days post-induction, resulting in death after 10 days. This phenotype is reminiscent of proliferative defects.In parallel, we address the possibility of a therapeutic window to target RPAP3 during intestinal tumorigenesis by using heterozygous animals (RPAP3 fl/+; Villin>Cre-ERT2 ) in which tumorignesis is induced (i) either by a chemical treatment : for this, we take advantage of the established AOM /DSS protocol, or, (ii) by a genetic one ( Apc LoxP/+).These ongoing experiments will address the role of R2TP in a tissue with a constant turnover and the relevance of R2TP in tumorigenesis.; La protéine chaperon HSP90 a de nombreux substrats par les voies de signalisations. Son inhibition engendre un effet tumoral. L'identification du complexe R2TP,un nouveau cochaperon d'HSP90, a mis en évidence de nouveaux substrats. Le système HSP90/R2TP est impliqué dans l'assemblage de complexes macromoléculaires ( PIKKs, Télomérase RNP, ARN polyméras, snoRNP) jouant un rôle clé dans la prolifération cellulaire et la tumorigénèse. Le R2TP est composé de 4 protéines : RUVBL1, RUVBL2, RPAP3 et PIH1D1 dont certains sont surexprimés dans les cancers hépatocellulaires ou colorectaux. Afin d'étudier le rôle du R2TP dans l'homéostasie intestinale et la carcinogénèse, nous avons généré un modèle d'invalidation de RPAP3 chez la souris. L'invalidation de RPAP3 dans l'organisme entier est létale. Son invalidation à l'âge adulte uniquement dans l'intestin entraine une phénotype sévère en 8jours aboutissant à la mort des individus à 10jours. En parallèle, nous avons étudié le rôle potentiel de RPAP3 dans la tumorigénèse intestinale et colorectale avec deux modèles d'induction , génétique avec l'invalidation du gène APC et chimique avec le protocole AOM/DSS.

Many substrates of HSP90 are involved in signal transduction pathways and related to tumour progression. Inhibition of HSP90 has anti-tumoral effects. Identification of the R2TP, a new HSP90 co-chaperon, allowed the identification of a new set of HSP90 substrates. HSP90/R2TP is involved in the assembly of snoRNPs, telomerase RNP, the nuclear RNA polymerases and PIKKs, which play key functions in cellular proliferation and tumorigenesis. R2TP is formed of four proteins: RUVBL1, RUVBL2, PIH1D1 and RPAP3, some of which are overexpressed in hepatocellular and colorectal cancer. We thus hypothesize that the co-chaperone R2TP could be involved in colorectal carcinogenesis.To study the role of R2TP in intestinal homeostasis and carcinogenesis, we generated a conditional knock-out murine model for RPAP3. We showed that RPAP3 invalidation in whole organism or only in colon is lethal at embryonic stage. The invalidation of RPAP3 in adult intestine, using an inducible recombinase (RPAP3 fl; Villin>Cre-ERT2), leads to a drastic phenotype as soon as 8 days post-induction, resulting in death after 10 days. This phenotype is reminiscent of proliferative defects.In parallel, we address the possibility of a therapeutic window to target RPAP3 during intestinal tumorigenesis by using heterozygous animals (RPAP3 fl/+; Villin>Cre-ERT2 ) in which tumorignesis is induced (i) either by a chemical treatment : for this, we take advantage of the established AOM /DSS protocol, or, (ii) by a genetic one ( Apc LoxP/+).These ongoing experiments will address the role of R2TP in a tissue with a constant turnover and the relevance of R2TP in tumorigenesis.; La protéine chaperon HSP90 a de nombreux substrats par les voies de signalisations. Son inhibition engendre un effet tumoral. L'identification du complexe R2TP,un nouveau cochaperon d'HSP90, a mis en évidence de nouveaux substrats. Le système HSP90/R2TP est impliqué dans l'assemblage de complexes macromoléculaires ( PIKKs, Télomérase RNP, ARN polyméras, snoRNP) jouant un rôle clé dans la prolifération cellulaire et la tumorigénèse. Le R2TP est composé de 4 protéines : RUVBL1, RUVBL2, RPAP3 et PIH1D1 dont certains sont surexprimés dans les cancers hépatocellulaires ou colorectaux. Afin d'étudier le rôle du R2TP dans l'homéostasie intestinale et la carcinogénèse, nous avons généré un modèle d'invalidation de RPAP3 chez la souris. L'invalidation de RPAP3 dans l'organisme entier est létale. Son invalidation à l'âge adulte uniquement dans l'intestin entraine une phénotype sévère en 8jours aboutissant à la mort des individus à 10jours. En parallèle, nous avons étudié le rôle potentiel de RPAP3 dans la tumorigénèse intestinale et colorectale avec deux modèles d'induction , génétique avec l'invalidation du gène APC et chimique avec le protocole AOM/DSS.