Abstract 3157: p53 inactivation and STAT2 cooperate to enhance migration and metastasis of colon tumor cells

STAT2 is a pivotal signaling component in the antiviral and antiproliferative effects of type I and type III interferon (IFN), but its role in cancer remains understudied. To date, only IFNs are known to activate STAT2. Work by us and others has demonstrated that STAT2 deficiency impairs the antitumor effects of type I IFN, supporting its role in suppressing tumor growth. With the availability of Stat2-/- mice, we interrogated the tumor-suppressive role of STAT2 by employing the AOM/DSS model of colitis-associated cancer and the spontaneous Apc Min/+ model of colorectal cancer (CRC). In both cancer models, loss of STAT2 reduced the number of adenomas, showing that under specific conditions STAT2 can be tumorigenic. Next, immunohistochemical staining of human normal colon and CRC tumors revealed elevated STAT2 protein in both adenomas and adenocarcinomas, suggesting that STAT2 is implicated in human CRC. Conversion of adenomas to adenocarcinomas is linked to loss of p53 function, which occurs in >50% of colorectal cancers. Therefore, we evaluated whether STAT2 altered the aggressive phenotype of p53-deficient colon carcinoma cells. We silenced STAT2 in isogenic p53 null and p53 wild-type tumor cells. STAT2 knockdown in p53 null colon carcinoma cells reduced migration of 3D tumor spheroids and tumor colony formation while no effect was seen in p53 wild-type tumor cells. We also observed that STAT2 knockdown in p53 null tumor cells increased protein levels of the marker of epithelial-mesenchymal transition, E-cadherin. Conversely, overexpression of STAT2 in p53 null cells reduced E-cadherin protein. In vivo, STAT2 knockdown delayed subcutaneous tumor growth of p53 null tumor cells. Furthermore, using an experimental liver metastasis tumor model, STAT2 knockdown abrogated the formation of tumor nodules in the liver. RNA-seq profiling of subcutaneous p53 null tumors revealed a subset of genes that were differentially expressed in a STAT2-dependent manner. Clinically, analysis of the TCGA database showed a STAT2 transcriptional signature in colorectal tumors that we are presently correlating with p53 alterations. Overall, we conclude that STAT2 enhances tumor growth and can contribute to disease progression by promoting migration and invasion when normal p53 function is lost. Citation Format: Ana M. Gamero, Kevin Kotredes, Aliza Abezis, Sruthi R. Gohimukkula, Alexandra Afanassiev, Tess Cremers, John J. Swain. p53 inactivation and STAT2 cooperate to enhance migration and metastasis of colon tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3157.