TY - JOUR
T1 - Reversible Myc hypomorphism identifies a key Myc-dependency in early cancer evolution
AU - Sodir, Nicole M
AU - Pellegrinet, Luca
AU - Kortlever, Roderik M.
AU - Campos, Tania
AU - Kwon, Yong-Won
AU - Kim, Shinseog
AU - Garcia, Daniel
AU - Perfetto, Alessandra
AU - Anastasiou, Panayiotis
AU - Swigart, Lamorna Brown
AU - Arends, Mark J
AU - Littlewood, Trevor D.
AU - Evan, Gerard I
N1 - Publisher Copyright:
© 2022. The Author(s).
Funding Information:
We thank the members of the Evan laboratory for invaluable discussion and advice. We also thank Stephanie Whike, Michaela Griffin and Deborah Breiner for assistance with histology and genotyping. The study was supported by Cancer Research UK programme grants (C4750/A12077, C4750/A19013A, and C4750/A29210), a European Research Council Advanced Investigator Award (294851), and a Stand Up To Cancer-Cancer Research UK-Lustgarten Foundation Pancreatic Cancer Dream Team Research Grant (SU2C-AACR-DT20-16), all to G.I.E. Stand Up To Cancer is a division of the Entertainment Industry Foundation and the research grant is administered by the American Association for Cancer Research, the Scientific Partner of SU2C.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/11/9
Y1 - 2022/11/9
N2 - 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
AB - 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
KW - Myc hypomorphism
KW - Myc bottleneck
KW - lung cancer
KW - pancreatic cancer
U2 - 10.1038/s41467-022-34079-x
DO - 10.1038/s41467-022-34079-x
M3 - Article
C2 - 36351945
SN - 2041-1723
VL - 13
SP - 6782
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6782
ER -