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

• Published in: Nature communications Vol. 14; no. 1; p. 1591
• Main Authors: Bai, Yuchen, Gotz, Carolin, Chincarini, Ginevra, Zhao, Zixuan, Slaney, Clare, Boath, Jarryd, Furic, Luc, Angel, Christopher, Jane, Stephen M., Phillips, Wayne A., Stacker, Steven A., Farah, Camile S., Darido, Charbel
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.03.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/1; 13/105; 13/109; 13/31; 13/51; 14/19; 14/5; 49/88; 631/67/1536; 631/80/84/2176; 96/106; 96/95; Cancer; Cell Line, Tumor; Cell Movement; Cell proliferation; Cell Proliferation - genetics; Epithelial cells; Epithelial Cells - metabolism; Epithelial-Mesenchymal Transition - genetics; Epithelium; Head & neck cancer; Humanities and Social Sciences; Humans; Inactivation; Metastases; Molecular modelling; multidisciplinary; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Proteomes; Proto-Oncogene Proteins c-akt - metabolism; Science; Science (multidisciplinary); Signal Transduction; Signaling; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Tumors; Y-Box-Binding Protein 1 - genetics; Y-Box-Binding Protein 1 - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-37161-0

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. The understanding of molecular mechanisms in different subtypes of head and neck cancer (HNC) will define subtype-specific treatment options. Here the authors show that PI3K-phospho-YBX1 axis promotes tumour growth in basal subtype of HNC, while unphosphorylated YBX1 acts as a suppressor of metastasis in the mesenchymal subtype with inactive PI3K signalling.