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

Author

Listed:
  • Yuchen Bai

    (Peter MacCallum Cancer Centre)

  • Carolin Gotz

    (Technische Universität München, Fakultät für Medizin, Klinikum rechts der Isar
    Medizinische Universität Innsbruck)

  • Ginevra Chincarini

    (Peter MacCallum Cancer Centre)

  • Zixuan Zhao

    (Sun Yat-sen University Cancer Center, Yuexiu District)

  • Clare Slaney

    (Peter MacCallum Cancer Centre
    The University of Melbourne)

  • Jarryd Boath

    (Peter MacCallum Cancer Centre)

  • Luc Furic

    (Peter MacCallum Cancer Centre
    The University of Melbourne
    Monash University)

  • Christopher Angel

    (Peter MacCallum Cancer Centre)

  • Stephen M. Jane

    (Monash University)

  • Wayne A. Phillips

    (Peter MacCallum Cancer Centre
    The University of Melbourne)

  • Steven A. Stacker

    (Peter MacCallum Cancer Centre
    The University of Melbourne)

  • Camile S. Farah

    (CQ University)

  • Charbel Darido

    (Peter MacCallum Cancer Centre
    The University of Melbourne)

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.

Suggested Citation

  • 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 &, 2023. "YBX1 integration of oncogenic PI3K/mTOR signalling regulates the fitness of malignant epithelial cells," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37161-0
    DOI: 10.1038/s41467-023-37161-0
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    References listed on IDEAS

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    1. Ashok Kumar Jayavelu & Tina M. Schnöder & Florian Perner & Carolin Herzog & Arno Meiler & Gurumoorthy Krishnamoorthy & Nicolas Huber & Juliane Mohr & Bärbel Edelmann-Stephan & Rebecca Austin & Sabine , 2020. "Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms," Nature, Nature, vol. 588(7836), pages 157-163, December.
    2. K. Yu & B. Chen & D. Aran & J. Charalel & C. Yau & D. M. Wolf & L. J. ‘t Veer & A. J. Butte & T. Goldstein & M. Sirota, 2019. "Comprehensive transcriptomic analysis of cell lines as models of primary tumors across 22 tumor types," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
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