The sporadic transition from indolent to metastatic disease is a hallmark of prostate cancer (PC) and frequently involves deletion of PTEN and TP53. We recently recapitulated metastasis of Pten/ Trp53-mutant PC in mouse using the RapidCaP system and surprisingly, we found that it is driven by Myc, rather than Akt activation.

Here, we show that cell-cell communication by Il6 drives this Akt-Myc switch through activation of the Akt-inactivating phosphatase Phlpp2. Primary cells revealed that loss of Pten/ Trp53 triggers secretion of the Il6 cytokine when these genes are deleted together, but not separately. Il6 then communicates a downstream program of Stat3-mediated Myc activation, which drives cell proliferation. Abrogation of Myc activity by Myc inhibition with the JQ1 bromodomain inhibitor, Myc-RNAi, and Myc-CRISPR/ Cas9 approaches inhibited proliferation. We validated these findings in vivo, where peak proliferation in Pten/ Trp53 mutant primary and metastatic PC did not correlate with activated Akt, but with Stat3/ Myc activation instead. Most notably, we found that Myc strongly activates the Akt phosphatase Phlpp2 in primary cells and RapidCaP metastasis, and showed genetically that Phlpp2 is essential for dictating proliferation and Myc-mediated suppression of Akt.

Collectively, our data reveal competition between two proto-oncogenes: Myc and Akt, which ensnarls the Phlpp2 gene to facilitate Myc-driven metastasis.

Citation Format: Dawid G. Nowak, Hyejin Cho, Tali Herzka, Victoria M.Y. Wang, Serif Senturk, Daniel V. DeMarco, David Ding, Christof Fellmann, Tumas Beinortas, David Kleinman, Kaitlin Watrud, Muhan Chen, John E. Wilkinson, Mireia Castillo-Martin, Carlos Cordon-Cardo, Brian D. Robinson, Lloyd C. Trotman. Myc drives Pten/ p53-deficient proliferation and metastasis due to Il6-secretion and Akt-suppression via Phlpp2. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2258. doi:10.1158/1538-7445.AM2015-2258