LAUSR

Intestinal type gastric cancer develops within metaplastic mucosal fields and development of gastric neoplasia represents the most prominent example of gastric cancer developing within the morphologic changes of metaplasia. Recent investigations have noted activation of Ras activity in up to 40% of human gastric cancers and suggest. Our recent study has suggested that chief cells might be an origin of gastric cancer using a mouse model, Mist1-CreERT2;LSL-KRas(G12D) mouse (Mist1-Kras).  The Mist1-Kras mice rapidly developed SPEM and IM within 3 months and invasive metaplasia within 4 months following induction of constitutively-active Kras(G12D) expression in the chief cells in the mouse stomach. We also observed regression of metaplasia by targeting downstream mediators of Kras signaling using a MEK inhibitor, Selumetinib. We therefore have now investigated how the progression and proliferation of metaplasia can be controlled. In this study, we have established metaplastic organoid lines (Meta3 and Meta4) from Mist1-Kras mouse stomach mucosa at 3 or 4 months after tamoxifen induction. We examined these organoids to understand the mechanisms of metaplasia progression through MEK inhibition.  Both Meta3 and Meta4 organoids have formed distinguishable glandular structures in 3D cultures and maintained a stable phenotype observed in metaplastic glands in the Mist1-Kras mouse stomachs. The MEK inhibition with Selumetinib in the metaplastic organoids inhibited growth, but promoted differentiation of metaplastic cells toward intestinal absorptive cells with elaboration of an apical brush border. Single cell RNA sequencing data revealed that Meta-4 have distinct characteristics that differ from Meta3. In 3D culture, Meta4 organoids developed more aggressive phenotypes than Meta3 and expressed Cortactin, which has critical roles in cancer cell migration and metastasis. Cortactin localized at the lamellipodia in monolayer culture of Meta4. Meta4 organoids treated with Selumetinib produced significantly fewer colonies in soft agar and resulted in loss of lamellipodia localization of Cortactin. Our results indicate that gastric carcinogenesis can be controlled by a MEK inhibitor, Selumetinib, and support the concept that growth of pre-neoplastic metaplasia and early stage gastric cancer in humans might be controlled with administration of Selumetinib. Citation Format: Eunyoung Choi, Amy C. Engevik, James R. Goldenring. Active Kras induced metaplasia progression toward gastric neoplasia is suppressed by MEK inhibition during gastric carcinogenesis [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 4095.