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

Yuchen Bai, Carolin Gotz, Ginevra Chincarini, Zixuan Zhao, Clare Slaney, Jarryd Boath, Luc Furic, Christopher Angel, Stephen M. Jane, Wayne A. Phillips, Steven A. Stacker, Camile S. Farah and Charbel Darido ()
Additional contact information
Yuchen Bai: Peter MacCallum Cancer Centre
Carolin Gotz: Technische Universität München, Fakultät für Medizin, Klinikum rechts der Isar
Ginevra Chincarini: Peter MacCallum Cancer Centre
Zixuan Zhao: Sun Yat-sen University Cancer Center, Yuexiu District
Clare Slaney: Peter MacCallum Cancer Centre
Jarryd Boath: Peter MacCallum Cancer Centre
Luc Furic: Peter MacCallum Cancer Centre
Christopher Angel: Peter MacCallum Cancer Centre
Stephen M. Jane: Monash University
Wayne A. Phillips: Peter MacCallum Cancer Centre
Steven A. Stacker: Peter MacCallum Cancer Centre
Camile S. Farah: CQ University
Charbel Darido: Peter MacCallum Cancer Centre

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37161-0

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