Graduate Student Pohang University of Science and Technology (POSTECH), Kyongsang-bukto, Republic of Korea
Abstract: WNT signaling plays a crucial role in cancer development, with APC as the primary tumor suppressor in colon cancer. Even though WNT signaling is still essential for maintaining the gastric epithelium and driving tumor progression, mechanisms of WNT self-sufficiency in gastric cancer remain unclear, as APC and CTNNB1 mutations are relatively rare. Using human and mouse gastric organoids and in vivo mouse models, we found that mesenchymal WNTs maintain normal gastric epithelium, while KRAS activation induces epithelial WNT secretion, enabling WNT self-sufficiency. Single-cell multi-omics revealed that KRAS-driven MAPK signaling activates SMAD2/3 and unlocks the WNT7B locus, generating WNT7B+ niche cells within the epithelium. In human gastric cancer, HER2-KRAS-MAPK activation or WNT2 amplification drives epithelial WNT production. Our findings identify epithelial WNT secretion as a key mechanism of WNT self-sufficiency in gastric tumorigenesis. Unlike APC or CTNNB1 mutations in colon cancer, this process is targetable, offering potential therapeutic opportunities
Funding Source: This research was supported by the National Research Foundation of Korea(NRF) funded by the Korea Government(MSIT)(No.RS-2024-00431505) and SCORPION program_FWF DOC72 (Doi :10.55776/DOC72)
