Journal
CANCER GENE THERAPY
Volume 29, Issue 10, Pages 1463-1476Publisher
SPRINGERNATURE
DOI: 10.1038/s41417-022-00454-5
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ERG translocations play a key role in the initiation of prostate neoplasia. However, the mechanisms of oncogenic inception have not been fully understood. In this study, a genetically engineered mouse model was used to investigate the effects of combined TMPRSS2-driven ERG and Kras(G12D) on prostate adenocarcinomas. It was found that the presence of TMPRSS2-ERG, along with Kras(G12D), promoted tumorigenesis and metastasis of primary luminal cells. Additionally, TMPRSS2-ERG suppressed oncogene-induced senescence, leading to the accumulation of additional gene mutations. This study reveals a previously unknown function of ERG expression in priming preneoplastic cells for oncogenic mutations.
ERG translocations are commonly involved in the initiation of prostate neoplasia, yet previous experimental approaches have not addressed mechanisms of oncogenic inception. Here, in a genetically engineered mouse model, combining TMPRSS2-driven ERG with Kras(G12D) led to invasive prostate adenocarcinomas, while ERG or Kras(G12D) alone were non-oncogenic. In primary prostate luminal epithelial cells, following inducible oncogenic Kras expression or Pten depletion, TMPRSS2-ERG suppressed oncogene-induced senescence, independent of TP53 induction and RB1 inhibition. Oncogenic KRAS and TMPRSS2-ERG synergized to promote tumorigenesis and metastasis of primary luminal cells. The presence of TMPRSS2-ERG compared to a wild-type background was associated with a stemness phenotype and with relatively increased RAS-induced differential gene expression for MYC and mTOR-regulated pathways, including protein translation and lipogenesis. In addition, mTOR inhibitors abrogated ERG-dependent senescence resistance. These studies reveal a previously unappreciated function whereby ERG expression primes preneoplastic cells for the accumulation of additional gene mutations by suppression of oncogene-induced senescence.
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