Amiaud, J. | bioRxiv Science

bioRxiv2023

Chimeric protein EWS-FLI1 drives cell proliferation in Ewing Sarcoma via overexpression of KCNN1.

Ewing sarcoma (ES) is characterized by chimeric fusion proteins, which act as oncogenes. Over the last decade, patient survival has not increased, especially for high risk patients. Knowing that ion channels are studied for their implication in tumorigenesis, the aim of this work is to study the involvement of the SK1 potassium channels in ES. RNA-Seq analyses showed a high restricted expression of KCNN1, the gene encoding SK1, only in ES patients, and its expression is inversely correlated with patient survival. EWS-FLI1 silencing demonstrated the regulation of KCNN1 by these fusion proteins, which bind at GGAA microsatellites near KCNN1 promoter. In addition, KCNN1 has been shown to be involved in the regulation of ES cell proliferation, its silencing being associated with a slowing of the cell cycle. Finally, KCNN1 expression modulates membrane potential and calcium flux suggesting the role of calcium in KCNN1 driving cell proliferation. These results highlight that KCNN1 is a direct EWS-FLI1 and EWS-ERG target, and is involved in the regulation of ES cell proliferation, making it an interesting therapeutic target in ES.

cancer biology↗

bioRxiv2022

Specific targeting of inflammatory osteoclastogenesis by the probiotic yeast S. boulardii CNCM I-745 reduces bone loss in osteoporosis

Bone destruction is a hallmark of chronic inflammation, and bone-resorbing osteoclasts arising under such a condition differ from steady-state ones. However, osteoclast diversity remains poorly explored. Here, we combined transcriptomic profiling, differentiation assays and in vivo analysis in mouse to decipher specific traits for inflammatory and steady state osteoclasts. We identified and validated the pattern-recognition receptors (PRR) TLR2, Dectin-1 and Mincle, all involved in yeast recognition as major regulators of inflammatory osteoclasts. We showed that administration of the yeast probiotic Saccharomyces boulardi CNCM I-745 (Sb) in vivo reduced bone loss in OVX but not sham mice by reducing inflammatory osteoclasts. This beneficial impact of Sb is mediated by the regulation of the inflammatory environment required for the generation of inflammatory osteoclasts. We also showed that Sb derivatives as well as agonists of TLR2, Dectin-1 and Mincle specifically inhibited directly the differentiation of inflammatory but not steady state osteoclasts in vitro. These findings demonstrate a preferential use of the PRR-associated costimulatory differentiation pathway by inflammatory osteoclasts, thus enabling their specific inhibition, which opens new therapeutic perspectives for inflammatory bone loss.

physiology↗