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Reversible Myc hypomorphism identifies a key Myc-dependency in early cancer evolution

Author

Listed:
  • Nicole M. Sodir

    (University of Cambridge
    Genentech, Department of Translational Oncology)

  • Luca Pellegrinet

    (University of Cambridge)

  • Roderik M. Kortlever

    (University of Cambridge)

  • Tania Campos

    (University of Cambridge)

  • Yong-Won Kwon

    (Abcam, 860 Auburn Ct)

  • Shinseog Kim

    (Center for Genomic Integrity, Institute for Basic Science)

  • Daniel Garcia

    (Oncogenesis Thematic Research Center at Bristol Myers Squibb)

  • Alessandra Perfetto

    (University of Cambridge)

  • Panayiotis Anastasiou

    (University of Cambridge)

  • Lamorna Brown Swigart

    (University of California)

  • Mark J. Arends

    (University of Edinburgh)

  • Trevor D. Littlewood

    (University of Cambridge)

  • Gerard I. Evan

    (University of Cambridge
    The Francis Crick Institute)

Abstract

Germ-line hypomorphism of the pleiotropic transcription factor Myc in mice, either through Myc gene haploinsufficiency or deletion of Myc enhancers, delays onset of various cancers while mice remain viable and exhibit only relatively mild pathologies. Using a genetically engineered mouse model in which Myc expression may be systemically and reversibly hypomorphed at will, we asked whether this resistance to tumour progression is also emplaced when Myc hypomorphism is acutely imposed in adult mice. Indeed, adult Myc hypomorphism profoundly blocked KRasG12D-driven lung and pancreatic cancers, arresting their evolution at the early transition from indolent pre-tumour to invasive cancer. We show that such arrest is due to the incapacity of hypomorphic levels of Myc to drive release of signals that instruct the microenvironmental remodelling necessary to support invasive cancer. The cancer protection afforded by long-term adult imposition of Myc hypomorphism is accompanied by only mild collateral side effects, principally in haematopoiesis, but even these are circumvented if Myc hypomorphism is imposed metronomically whereas potent cancer protection is retained.

Suggested Citation

  • Nicole M. Sodir & Luca Pellegrinet & Roderik M. Kortlever & Tania Campos & Yong-Won Kwon & Shinseog Kim & Daniel Garcia & Alessandra Perfetto & Panayiotis Anastasiou & Lamorna Brown Swigart & Mark J. , 2022. "Reversible Myc hypomorphism identifies a key Myc-dependency in early cancer evolution," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34079-x
    DOI: 10.1038/s41467-022-34079-x
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    References listed on IDEAS

    as
    1. Megan J. Bywater & Deborah L. Burkhart & Jasmin Straube & Arianna Sabò & Vera Pendino & James E. Hudson & Gregory A. Quaife-Ryan & Enzo R. Porrello & James Rae & Robert G. Parton & Theresia R. Kress &, 2020. "Reactivation of Myc transcription in the mouse heart unlocks its proliferative capacity," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
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    3. Andreas Trumpp & Yosef Refaeli & Thordur Oskarsson & Stephan Gasser & Mark Murphy & Gail R. Martin & J. Michael Bishop, 2001. "c-Myc regulates mammalian body size by controlling cell number but not cell size," Nature, Nature, vol. 414(6865), pages 768-773, December.
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