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Non-canonical functions of SNAIL drive context-specific cancer progression

Author

Listed:
  • Mariel C. Paul

    (German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
    Technische Universität München)

  • Christian Schneeweis

    (German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
    Technische Universität München
    Technische Universität München
    Technical University of Munich)

  • Chiara Falcomatà

    (German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
    Technische Universität München
    Technical University of Munich)

  • Chuan Shan

    (German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
    Technische Universität München)

  • Daniel Rossmeisl

    (German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
    Technische Universität München
    Technical University of Munich)

  • Stella Koutsouli

    (Faculty of Medicine, LMU Munich)

  • Christine Klement

    (Technical University of Munich
    Technische Universität München
    German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Munich)

  • Magdalena Zukowska

    (German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
    Technische Universität München
    Technical University of Munich)

  • Sebastian A. Widholz

    (Technical University of Munich
    Technische Universität München
    German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Munich)

  • Moritz Jesinghaus

    (German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
    Technische Universität München
    Technical University of Munich
    Technische Universität München)

  • Konstanze K. Heuermann

    (German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
    Technische Universität München
    Technical University of Munich)

  • Thomas Engleitner

    (Technical University of Munich
    Technische Universität München
    German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Munich)

  • Barbara Seidler

    (German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
    Technische Universität München
    Technical University of Munich)

  • Katia Sleiman

    (German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
    Technische Universität München
    Technical University of Munich)

  • Katja Steiger

    (Technische Universität München)

  • Markus Tschurtschenthaler

    (German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
    Technische Universität München
    Technical University of Munich)

  • Benjamin Walter

    (Technische Universität München)

  • Sören A. Weidemann

    (German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
    Technische Universität München
    Technical University of Munich)

  • Regina Pietsch

    (German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
    Technische Universität München
    Technical University of Munich)

  • Angelika Schnieke

    (Technische Universität München)

  • Roland M. Schmid

    (Technische Universität München)

  • Maria S. Robles

    (Faculty of Medicine, LMU Munich)

  • Geoffroy Andrieux

    (University of Freiburg
    Partner Site Freiburg)

  • Melanie Boerries

    (University of Freiburg
    Partner Site Freiburg)

  • Roland Rad

    (Technical University of Munich
    Technische Universität München
    German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Munich)

  • Günter Schneider

    (German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
    Technische Universität München
    Technical University of Munich
    Visceral and Pediatric Surgery)

  • Dieter Saur

    (German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
    Technische Universität München
    Technische Universität München
    Technical University of Munich)

Abstract

SNAIL is a key transcriptional regulator in embryonic development and cancer. Its effects in physiology and disease are believed to be linked to its role as a master regulator of epithelial-to-mesenchymal transition (EMT). Here, we report EMT-independent oncogenic SNAIL functions in cancer. Using genetic models, we systematically interrogated SNAIL effects in various oncogenic backgrounds and tissue types. SNAIL-related phenotypes displayed remarkable tissue- and genetic context-dependencies, ranging from protective effects as observed in KRAS- or WNT-driven intestinal cancers, to dramatic acceleration of tumorigenesis, as shown in KRAS-induced pancreatic cancer. Unexpectedly, SNAIL-driven oncogenesis was not associated with E-cadherin downregulation or induction of an overt EMT program. Instead, we show that SNAIL induces bypass of senescence and cell cycle progression through p16INK4A-independent inactivation of the Retinoblastoma (RB)-restriction checkpoint. Collectively, our work identifies non-canonical EMT-independent functions of SNAIL and unravel its complex context-dependent role in cancer.

Suggested Citation

  • Mariel C. Paul & Christian Schneeweis & Chiara Falcomatà & Chuan Shan & Daniel Rossmeisl & Stella Koutsouli & Christine Klement & Magdalena Zukowska & Sebastian A. Widholz & Moritz Jesinghaus & Konsta, 2023. "Non-canonical functions of SNAIL drive context-specific cancer progression," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36505-0
    DOI: 10.1038/s41467-023-36505-0
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    References listed on IDEAS

    as
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