Abstract 186: Tumor cell-intrinsic STAT2 signaling contributes to mitochondrial energetics in colorectal cancer

Abstract Colorectal cancer (CRC) is the 3rd most common cancer type in the US, with an alarming increase in incidence rates in young adults that is preventable when detected early. Identifying the molecular culprits involved in promoting CRC is urgently needed to design novel therapeutic interventions to combat this disease. Signal transducer and activator of transcription 2 (STAT2) is a key transcription factor that uniquely mediates the antitumor effects of type I and III interferons (IFNs), a family of pleiotropic cytokines, by activating the transcription of genes involved in restricting tumor growth. Much of what is known about STAT2 is in the context of IFN signaling. Yet, the precise function of STAT2 in cancer is understudied. New evidence shows that STAT2 has opposing biological effects in cancer. We and others have reported that STAT2 inhibits tumor cell proliferation and induces apoptosis in response to IFNs. Conversely, our new data finds that STAT2 promotes tumor growth in pre-clinical models of CRC (spontaneous and tumor xenografts) by a mechanism that is still unidentified. To begin to elucidate the pro-tumorigenic effects of STAT2, we analyzed the human colon adenocarcinoma TCGA datasets for an association with overall survival and alterations in transcriptional signatures between high and low STAT2 expression levels. First, we found a correlation between high STAT2 levels and poor survival. Second, out of the 42 hallmark gene set pathways significantly enriched, oxidative phosphorylation (OXPHOS) was strikingly downregulated in STAT2-high tumors. We performed mitochondrial and glycolysis stress tests to determine changes in cellular energetics between parental and STAT2 deficient (STAT2KO) human HCT116 colon adenocarcinoma cells. Compared to parental tumor cells, STAT2 KO tumor cells had lower glycolytic capacity but increased maximal respiration and spare respiratory capacity. We next assessed the role of STAT2 in mitochondrial homeostasis because loss of STAT2 had been previously reported to interfere with mitochondrial fission. We determined by western blot analysis the activation status of Dynamin-related protein-1 (Drp1), a key protein that regulates mitochondrial fission. We found impaired activation of Drp1 in STAT2 KO tumor cells. Drp1 phosphorylation was reduced at activatory serine 616 and increased at inhibitory serine 627. Overall, our findings are first to indicate that STAT2 in CRC may be involved in disrupting mitochondrial respiration and favoring glycolysis, a hallmark of cancer, to promote CRC. This paves the way for determining whether the tumor promoting effects of STAT2 are dictated at the mitochondrial level by disrupting OXPHOS and whether this is occurring independently of IFN signaling. Studies are ongoing to determine whether other components of mitochondrial fission and kinases involved in Drp1 activation are also regulated by STAT2. Citation Format: Jorge Canar, Silvia Fossati, Michael Slifker, Ana M. Gamero. Tumor cell-intrinsic STAT2 signaling contributes to mitochondrial energetics in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 186.