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Zhao, Hua; Cheng, Yulan; Kalra, Andrew; Ma, Ke; Zheng, Yueyuan; Ziman, Benjamin; Tressler, Caitlin; Glunde, Kristine; Shin, Eun Ji; Ngamruengphong, Saowanee; Khashab, Mouen; Singh, Vikesh; Anders, Robert A; Jit, Simran; Wyhs, Nicolas; Chen, Wei; Li, Xu; Lin, De-Chen; Meltzer, Stephen J
Science translational medicine, 11/2022, Volume: 14, Issue: 673Journal Article
Inactivation of the tumor suppressor genes tumor protein p53 ( ) and cyclin-dependent kinase inhibitor 2A ( ) occurs early during gastroesophageal junction (GEJ) tumorigenesis. However, because of a paucity of GEJ-specific disease models, cancer-promoting consequences of and inactivation at the GEJ have not been characterized. Here, we report the development of a wild-type primary human GEJ organoid model and a CRISPR-edited transformed GEJ organoid model. CRISPR-Cas9-mediated and knockout ( ) in GEJ organoids induced morphologic dysplasia and proneoplastic features in vitro and tumor formation in vivo. Lipidomic profiling identified several platelet-activating factors (PTAFs) among the most up-regulated lipids in CRISPR-edited organoids. PTAF/PTAF receptor (PTAFR) abrogation by siRNA knockdown or a pharmacologic inhibitor (WEB2086) reduced proliferation and other proneoplastic features of GEJ organoids in vitro and tumor formation in vivo. In addition, murine xenografts of Eso26, an established human esophageal adenocarcinoma cell line, were suppressed by WEB2086. Mechanistically, dual inactivation disrupted both the transcriptome and the DNA methylome, likely mediated by key transcription factors, particularly forkhead box M1 (FOXM1). FOXM1 activated transcription by binding to the promoter, further amplifying the PTAF-PTAFR pathway. Together, these studies established a robust model system for investigating early GEJ neoplastic events, identified crucial metabolic and epigenomic changes occurring during GEJ model tumorigenesis, and revealed a potential cancer therapeutic strategy. This work provides insights into proneoplastic mechanisms associated with inactivation in early GEJ neoplasia, which may facilitate early diagnosis and prevention of GEJ neoplasms.
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