YBX1 integration of oncogenic PI3K/mTOR signalling regulates the fitness of malignant epithelial cells

Bai, Y; Gotz, C; Chincarini, G; Zhao, Z; Slaney, C; Boath, J; Furic, L; Angel, C; Jane, SM; Phillips, WA; Stacker, SA; Farah, CS; Darido, C

Author(s): Bai, Y; Gotz, C; Chincarini, G; Zhao, Z; Slaney, C; Boath, J; Furic, L; Angel, C; Jane, SM; Phillips, WA; Stacker, SA; Farah, CS; Darido, C;
Details: Publication Year 2023-03-22,Volume 14,Issue #1,Page 1591
Journal Title: Nature Communications
Publication Type: Research article
Abstract: In heterogeneous head and neck cancer (HNC), subtype-specific treatment regimens are currently missing. An integrated analysis of patient HNC subtypes using single-cell sequencing and proteome profiles reveals an epithelial-mesenchymal transition (EMT) signature within the epithelial cancer-cell population. The EMT signature coincides with PI3K/mTOR inactivation in the mesenchymal subtype. Conversely, the signature is suppressed in epithelial cells of the basal subtype which exhibits hyperactive PI3K/mTOR signalling. We further identify YBX1 phosphorylation, downstream of the PI3K/mTOR pathway, restraining basal-like cancer cell proliferation. In contrast, YBX1 acts as a safeguard against the proliferation-to-invasion switch in mesenchymal-like epithelial cancer cells, and its loss accentuates partial-EMT and in vivo invasion. Interestingly, phospho-YBX1 that is mutually exclusive to partial-EMT, emerges as a prognostic marker for overall patient outcomes. These findings create a unique opportunity to sensitise mesenchymal cancer cells to PI3K/mTOR inhibitors by shifting them towards a basal-like subtype as a promising therapeutic approach against HNC.
Publisher: Springer Nature
Keywords: Humans; *Phosphatidylinositol 3-Kinases/genetics/metabolism; *Proto-Oncogene Proteins c-akt/metabolism; Signal Transduction; TOR Serine-Threonine Kinases/genetics/metabolism; Cell Proliferation/genetics; Epithelial Cells/metabolism; Epithelial-Mesenchymal Transition/genetics; Cell Line, Tumor; Cell Movement; Y-Box-Binding Protein 1/genetics/metabolism
Department(s): Laboratory Research; Pathology
PubMed ID: 36949044
Publisher's Version: https://doi.org/10.1038/s41467-023-37161-0
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-023-37161-0
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-06-22 07:56:49

Last Modified: 2023-06-22 07:57:28