Biology subjects

Bremond, J.

Publications and source records attributed to Bremond, J..

3 recordsLinked to original sources

bioRxiv2019

Partial loss of colonic primary cilia promotes inflammation and carcinogenesis

Primary cilia (PC) are important signaling hubs in cells and their deregulation has been associated with various diseases including cancer. Here we explored the role of PC in colorectal cancer (CRC) and colitis. In the colon we found PC to be mostly present on different subtypes of fibroblasts. Colons of mice exposed to either chemically induced colitis-associated colon carcinogenesis (CAC) or dextran sodium sulfate (DSS)-induced colitis had decreased numbers of PC. We employed conditional knock-out strains for the PC essential genes, Kif3A and Ift88, to generate mice with reduced numbers of PC on colonic fibroblasts. These mice showed an increased susceptibility in the CAC model as well as in DSS-induced colitis. Colons from DSS-treated mice with PC-deficiency on fibroblasts displayed an elevated production of the pro-inflammatory cytokine IL-6 and colonic epithelial cells had diminished levels of HES-1, a key transcription factor of Notch signaling. Notably, an analysis of PC presence on biopsies of patients with ulcerative colitis as well as CRC patients revealed decreased numbers of PC on colonic fibroblasts in pathological versus surrounding normal tissue. Taken together, we provide evidence that a decrease in colonic PC numbers promotes colitis and CRC. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=177 HEIGHT=200 SRC="FIGDIR/small/871772v2_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1f8eccdorg.highwire.dtl.DTLVardef@1829b3borg.highwire.dtl.DTLVardef@19d632aorg.highwire.dtl.DTLVardef@1d9833b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2019

The R2TP chaperone assembles cellular machineries in intestinal CBC stem cells and progenitors

The R2TP chaperone cooperates with HSP90 to integrate newly synthesized proteins into multi-subunit complexes, yet its role in tissue homeostasis is unknown. Here, we generated conditional, inducible knock-out mice for Rpap3 to inactivate this core component of R2TP in the intestinal epithelium. In adult mice, Rpap3 invalidation caused destruction of the small intestinal epithelium, and death within 10 days. Levels of R2TP substrates were decreased, with strong effects on mTOR, ATM and ATR. Rpap3-deficient CBC stem cells and progenitors also failed to import RNA polymerase II in the nucleus. This correlated with p53 activation, cell cycle arrest and apoptosis. Interestingly, post-mitotic, differentiated cells did not display any of those alterations, indicating that R2TP clients are built in actively proliferating cells. Analyses of tissues from colorectal cancer patients revealed that high RPAP3 levels correlate with bad cancer prognosis. Thus, in the intestine, the R2TP chaperone functions in physiologic and pathologic proliferation.

developmental biology↗

bioRxiv2019

Loss of cyclin A2 in murine colonic epithelial cells disrupts colon homeostasis by triggering DNA damage and dysplasia and high cyclin A2 expression is a good-prognosis factor in patients with colorectal cancer

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 good prognosis factor independently from other prognostic factors for the CMS1, CMS3 and CMS4 subtypes.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC=\"FIGDIR/small/690404v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (36K):\norg.highwire.dtl.DTLVardef@d9de04org.highwire.dtl.DTLVardef@17f0b4forg.highwire.dtl.DTLVardef@1bf9748org.highwire.dtl.DTLVardef@16520df_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗