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Mograbi, B.

Publications and source records attributed to Mograbi, B..

2 recordsLinked to original sources

Comprehensive mapping of identical epitopes across human proteins reveals implications for immune recognition and therapeutic design

Shared epitopes create safety and efficacy issues for T-cell immunotherapy. In order to facilitate the monitoring of immune responses and the engineering required to solve this problem, we performed a computational proteome-wide epitope screening to establish the complete atlas of shared epitopes in the human and murine proteomes. Unlike bacterial or viral antigens, self-antigens like tumor-associated antigens (TAAs) frequently contained a high level of shared MHC-II epitopes identical to unintended other self-proteins. Therefore, shared epitopes should be a mandatory and systematic concern in studies using TAA. Noticeably, a subset of TAAs identified in this atlas is free of this drawback. Therefore, this dataset will be essential for immunologists designing cancer vaccines, but also to interpret immunomonitoring studies against self-antigens in oncology and autoimmunity. To facilitate the detection of common epitopes, a web server has been made available at https://epitopscanner.ircan.org/.

bioinformatics↗

Processing body dynamics drive non-genetic MEK inhibitors tolerance by fine-tuning KRAS and NRAS translation

Overactivation of the Mitogen-activated protein kinase (MAPK) pathway is a critical driver of many human cancers. However, therapies targeting this pathway have proven effective in only a few cancers, as cancers inevitably develop resistance. Puzzling observations suggest that MAPK targeting fails in tumors due to early compensatory RAS overexpression, albeit by unexplained mechanisms. We identified a novel mechanism of drug tolerance to MEK inhibitors (MEKi) that involves Processing Bodies (PBs), a membraneless organelle (MLO). MEKi promoted translation of the oncogenes KRAS and NRAS, which in turn triggered BRAF phosphorylation. This overexpression, which occurred in the absence of neotranscription, depended on PB dissolution as the source of the RAS mRNA. Moreover, in response to MEKi removal, the process was dynamic as PBs rapidly reformed and reduced MAPK signaling. These results highlight a dynamic spatiotemporal negative feedback loop of MAPK signaling via RAS mRNA sequestration. Furthermore, we observed a phenotype with a low number of PBs along with strong KRAS and NRAS induction capacities. Overall, we describe a new intricate mechanism involving PBs in the translational regulation of essential cellular signaling pathways like MAPKs, paving the way for future therapies altering MLO and thereby improving targeted cancer therapies.

cancer biology↗