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Mol. Cancer, Dec 16 2025, | https://doi.org/10.1186/s12943-025-02543-z Epithelial WNT secretion drives niche escape of developing gastric cancer

Jaehun Lee^1,2*, Soomin Kim^1,3*, Youngchul Oh^1,2*, Stephan R. Jahn^4*, Jihoon Kim^1,5*, Yeongjun Kim^1,3, Tim Schmäche^4,6, Sang-Min Kim⁷, Isaree Teriyapirom^8,9, Thomas Groß¹⁰, Ohbin Kwon^1,11, Jungmin Kim^12,13,14, Somi Kim², Anne-Marlen Ada⁴, Andrea Català-Bordes¹, Youngwon Cho^15,16, Jinho Kim^17,18,19, Amanda Andersson-Rolf⁸, Sebastian R. Merker⁴, Joo Yeon Lim¹², Ji-Yeon Park²⁰, Thomas M. Klompstra^1,11, Ki-Jun Yoon^1,11,21,22, Dae-Sik Lim^21,22, Ho-Seok Lee^1,3, Jong Kyoung Kim², Eunyoung Choi^15,16,23, James R. Goldenring^15,16,23,24, Jae-Ho Cheong^{12,13,14,25,26,27+}, Hyunki Kim⁷⁺, Daniel E. Stange^4,6,28+, Heetak Lee¹⁺, Bon-Kyoung Koo^1,2,11+, and Ji-Hyun Lee^1,29+

¹Center for Genome Engineering, Institute for Basic Sciences, Republic of Korea
²Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Republic of Korea
³Department of Biology, Kyung Hee University, Republic of Korea
⁴Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
⁵Department of Medical and Biological Sciences, The Catholic University of Korea, Bucheon, Republic of Korea
⁶National Center for Tumor Diseases (NCT), NCT/UCC Dresden, a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Germany.
⁷Department of Pathology, Yonsei University College of Medicine, Republic of Korea
⁸Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Austria
⁹Vienna BioCenter PhD Program, Doctoral School of the University of Vienna and Medical University of Vienna, Austria
¹⁰Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), NCT/UCC Dresden, a partnership between DKFZ, Faculty of Medicine and University Hospital Carl
Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Germany.
¹¹Graduate School of Stem Cell and Regenerative Biology, KAIST, Daejeon 34141, Republic of Korea
¹²Department of Surgery, Yonsei University College of Medicine, Republic of Korea
¹³Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, South Korea
¹⁴Department of Medical Science, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
¹⁵Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee
¹⁶Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee
¹⁷Precision Medicine Center, Future Innovation Research Division, Seoul National University Bundang Hospital (SNUBH), Seongnam, Gyeonggi‑do 13620, Republic of Korea.
¹⁸Department of Genomic Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi‑do 13620, Republic of Korea.
¹⁹Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Gyeonggi‑do 13620, Republic of Korea.
²⁰Gradiant Bioconvergence Inc., Seoul, Republic of Korea
²¹Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Republic of Korea
²²KAIST Stem Cell Center, KAIST, Daejeon 34141, Republic of Korea
²³Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee
²⁴Nashville VA Medical Center, Nashville, Tennessee
²⁵Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea
²⁶Chronic Intractable Disease for Systems Medicine Research Center, Yonsei University College of Medicine, Seoul, Republic of Korea
²⁷Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea
²⁸Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
²⁹Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Republic of Korea

^*These authors contributed equally to this work.
⁺Corresponding authors: Jae-Ho Cheong, Hyunki Kim, Daniel E. Stange, Heetak Lee, Bon-Kyoung Koo, and Ji-Hyun Lee

Abstract

Background: WNT signaling plays a key role in maintaining the gastric epithelium and promoting tumorigenesis. However, how gastric tumors achieve WNT niche independence remains unclear, as mutations on APC or CTNNB1-common mechanisms of ligand-independent WNT activation in colorectal cancer-are infrequent in gastric cancer. Understanding how WNT self-sufficiency is acquired in the stomach is therefore critical.

Methods: We analyzed mouse gastric organoids harboring oncogenic KRASG12D with or without RNF43/ZNRF3 (RZ) or CDH1/TP53 (CP) mutations, along with corresponding in vivo mouse models. Niche independence was assessed through growth factor withdrawal, Porcupine and pathway-specific inhibitor treatments, and WNT rescue assays. We performed single-nucleus multiome sequencing (RNA + ATAC) to investigate transcriptional and chromatin dynamics. Findings from mouse models were validated using patient-derived gastric cancer organoids, and pan-cancer cell line datasets were analyzed to evaluate clinical and cross-tissue relevance.

Results: Gastric fibroblasts secreted canonical WNT2B to maintain the homeostatic gastric epithelium. Upon KRAS activation, epithelial cells were reprogrammed to secrete WNT ligands independently of additional mutations. Single-nucleus multiome analysis revealed that KRAS-driven MAPK signaling opened SMAD2/3-bound enhancers at the WNT7B locus, leading to the emergence of WNT7B-expressing subpopulations. Inhibition of SMAD2/3 phosphorylation suppressed both organoid growth and WNT7B transcription, whereas exogenous WNT restored organoid proliferation. Patient-derived organoids with HER2 amplification, KRAS amplification, or WNT2 copy-number gain exhibited Porcupine inhibitor-sensitive growth, indicating dependence on WNT secretion from the organoids. Analysis of public transcriptomic datasets further demonstrated that the KRAS-MAPK-WNT7B axis is conserved across other cancer types, including lung cancer.

Conclusions: Gastric tumors can bypass niche dependence by acquiring KRAS-MAPK-SMAD2/3-driven epithelial WNT secretion. Targeting this axis-through MAPK inhibition, SMAD2/3 blockade, or suppression of WNT secretion-may represent a therapeutic vulnerability in gastric cancer and other KRAS-high malignancies.

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