Abstract 252: STAT3 signaling in the tumor microenvironment promotes primary gastric cancer growth and metastasis formation

Abstract Tumor cell intrinsic activation of Signal Transducer and Activator of Transcription 3 (STAT3) signaling has been shown to promote stemness, tumorigenesis and cancer therapy resistance. Therefore, Stat3 inhibitors are being developed and tested pre-clinically and in clinical trials for multiple solid cancers. Importantly, STAT3 signaling also occurs in the non-tumor cells within the tumor microenvironment (TME). The effect of Stat3 signaling within the TME on primary gastric cancers (GC), metastasis formation and therapy responses is unknown. Here, we describe a novel genetically defined, tumor organoid-driven, transplantable, orthotopic gastric cancer model that represents gastric carcinomas with associated metastasis formation in immune competent recipient mice. Utilizing our murine GC organoid model in subcutaneous allograft experiments, we showed that established GC tumors respond to pharmacological Stat3 inhibition. This anti-tumor effect is primarily driven by inhibition of the Stat3 signaling in the TME as tumor growth was increased in Stat3 high TME recipients, while tumor growth was inhibited in Stat3-signaling reduced Stat3+/- mice. Furthermore, Crisp-Cas9 -mediated Stat3 knockout in the GC organoids did not alter their in vitro growth potential. Stat3KO GC allograft tumor growth was not changed compared to Stat3WT GC tumors grown in wildtype host mice. Collectively, this suggests that inhibition of Stat3 signaling within the TME but not the tumor cell intrinsic Stat3 reduction confer anti-tumor responses. Through gastric serosa transplantation of the murine GC organoids into Stat3-elevated gp130FF mutant mice, we confirmed that high Stat3 signaling within the TME promotes distal metastasis formation to the liver. Taken together, we show that Stat3 signaling represents a therapy target, that predominantly acts through the TME. Better understanding of the signaling within the TME in primary and metastatic GC lesions will allow identification of novel tumor cell and TME-centric therapy targets. Combination of therapies targeting tumor cell intrinsic vulnerabilities with novel pro-tumorigenic TME -targeting agents could help to improve responses against primary and metastatic disease and therefore improve outcome for the worst prognosis patients. Citation Format: Moritz Eissmann, Anne Huber, Amr Allam, Christine Dijkstra, Matthias Ernst. STAT3 signaling in the tumor microenvironment promotes primary gastric cancer growth and metastasis formation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 252.