Abstract 277: Investigation of the signaling factors involved in Ras/MAPK-promoted metastasis in the PTEN − / − TP53 − / − mouse model.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC The most significant challenges for advanced prostate cancer patients are resistance to androgen-deprivation therapy and the dissemination of metastatic cancer cells. Our study begins to address how enhanced Ras signaling cooperates with combined TP53 and PTEN loss for enhanced metastatic capability. Because neither PTEN nor TP53 deletion alone is not sufficient for metastasis, we asked what other signaling pathways are required. Ras pathway activation is implicated in prostate cancer metastatic progression in comprehensive genetic analyses of human prostate tumors. We introduced a lentiviral vector expressing K-rasG12V into a non-metastatic PTEN−/−/TP53−/- adenocarcinoma cell line (clone 2). Orthotopic prostate injection of clone2/Ras expressing cells resulted in 100% pulmonary metastasis. The metastatic phenotype was paralleled by an inhibition of sarcomatoid carcinoma transformation. We hypothesized that Ras signaling modified TGFβ-mediated EMT signaling, which we have previously demonstrated leads to sarcomatoid carcinoma formation in this model. Multiple pathways downstream of TGFβ initiate signaling including SMAD4 dependent transcription and other non-SMAD mediated pathways like TAK1 induced NF-κB activation. Pathologic analysis of nuclear p65 labeling, a canonical NF-κB marker, showed enhanced labeling in clone2/Ras developed tumors and lung metastases and undetectable levels in clone 2 developed tumors. These in vivo findings suggest enhanced canonical NF-κB signaling may enable Ras transformed prostate cancer cells with metastatic capability. Citation Format: Heather S. Tillman, Juan Juan Yin, Yen Nien Liu, Musaddiq Awan, Philip Martin, Kathleen Kelly. Investigation of the signaling factors involved in Ras/MAPK-promoted metastasis in the PTEN −/− TP53 −/− mouse model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 277. doi:10.1158/1538-7445.AM2013-277