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

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 Arends, Trevor D. Littlewood, Gerard I Evan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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
Original languageEnglish
JournalNature Communications
Early online date9 Nov 2022
DOIs
Publication statusE-pub ahead of print - 9 Nov 2022

Keywords

  • Myc hypomorphism
  • Myc bottleneck
  • lung cancer
  • pancreatic cancer

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