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

• Published in: Nature communications Vol. 13; no. 1; p. 6782
• Main Authors: Sodir, Nicole M., Pellegrinet, Luca, Kortlever, Roderik M., Campos, Tania, Kwon, Yong-Won, Kim, Shinseog, Garcia, Daniel, Perfetto, Alessandra, Anastasiou, Panayiotis, Swigart, Lamorna Brown, Arends, Mark J., Littlewood, Trevor D., Evan, Gerard I.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09-11-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 38/1; 38/77; 38/91; 49; 631/67/2195; 631/80/304; 64; 64/110; 64/60; 82/51; Animals; c-Myc protein; Cancer; Cell Line, Tumor; Enhancers; Evolution; Gene deletion; Genes, ras; Genetic engineering; Haploinsufficiency; Humanities and Social Sciences; Invasiveness; Mice; multidisciplinary; Myc protein; Pancreatic cancer; Pancreatic Neoplasms - pathology; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Proto-Oncogene Proteins p21(ras) - genetics; Science; Science (multidisciplinary); Side effects; Transcription Factors - metabolism; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-34079-x

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 KRas
G12D
-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.
Happloinsufficiency of Myc delays onset of cancers in mice. Here, the authors generated a mouse model of reversible cMyc hypomorphism and show that metronomic reduction of c-Myc in adult mice confers protection against cancers without side effects and that the bottleneck in early cancer evolution is dependent upon Myc.