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TMPRSS2-ERG promotes the initiation of prostate cancer by suppressing oncogene-induced senescence

Cancer Gene Therapy volume 29, pages 1463–1476 (2022)Cite this article

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Abstract

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 KrasG12D led to invasive prostate adenocarcinomas, while ERG or KrasG12D 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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Fig. 1: TMPRSS2-ERG synergized with KrasG12D to promote invasive adenocarcinoma in an in vivo mouse model.
Fig. 2: Characterization of primary prostate epithelial cell lines.
Fig. 3: Suppression of KrasG12V-induced senescence by TMPRSS2-ERG.
Fig. 4: Suppression of KrasG12V-induced senescence by TMPRSS2-ERG.
Fig. 5: Overexpression of hERG in WT-1 cells reversed KrasG12V oncogene-induced senescence.
Fig. 6: TMPRSS2-ERG expression decreased PTEN depletion-induced senescence.
Fig. 7: Classical senescence signaling occurs in TP53 null but not in TP53 intact primary prostate luminal epithelial cells.
Fig. 8: Bioinformatics analysis of differentially expressed genes in WT-1 iKrasG12V and T-E-2 iKrasG12V after RAS induction at day 0, day 3, and day 5.

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Data availability

RNA-seq datasets generated and analyzed during the current study are deposited into the BioProject database with ID: PRJNA801601

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Acknowledgements

We thank Dr. Gianluca Pegoraro and Laurent Ozbun for their assistance at setting up and running Opera high throughput confocal imaging experiments and Neil Alilin for his assistance in managing mouse colonies and in vivo imaging.

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Authors and Affiliations

  1. Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, Bethesda, MD, USA

    Lei Fang, JuanJuan Yin, Joel Bowman, Brian Capaldo & Kathleen Kelly

  2. Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu, P. R. China

    Dongmei Li

  3. Department of Oncology, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang, P. R. China

    Hong Pan

  4. Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, CA, USA

    Huihui Ye

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Contributions

LF and KK conceived and designed the original research plans and supervised the research. LF, DL, and HP performed the experiments. JY performed in vivo orthotopic and intracardiac injections and supervised bioluminescent imaging of tumor growth. HY performed histological analysis of triple transgenic mice and evaluated IHC staining results. JB and BC analyzed RNA-seq data. LF and KK wrote the manuscript with contributions from all authors.

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Correspondence to Kathleen Kelly.

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Fang, L., Li, D., Yin, J. et al. TMPRSS2-ERG promotes the initiation of prostate cancer by suppressing oncogene-induced senescence. Cancer Gene Ther 29, 1463–1476 (2022). https://doi.org/10.1038/s41417-022-00454-5

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