Epithelial WNT secretion drives niche escape of developing gastric cancer

  • Mol Cancer. 2025 Dec 16;25(1):1. doi: 10.1186/s12943-025-02543-z.
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 Kim  7 ,  Isaree Teriyapirom  8  9 ,  Thomas Groß  10 ,  Ohbin Kwon  1  11 ,  Jungmin Kim  12  13  14 ,  Somi Kim  2 ,  Anne-Marlen Ada  4 ,  Andrea Català-Bordes  1 ,  Youngwon Cho  15  16 ,  Jinho Kim  17  18  19 ,  Amanda Andersson-Rolf  8 ,  Sebastian R Merker  4 ,  Joo Yeon Lim  12 ,  Ji-Yeon Park  20 ,  Thomas M Klompstra  1  11 ,  Ki-Jun Yoon  1  11  21  22 ,  Dae-Sik Lim  21  22 ,  Ho-Seok Lee  1  3 ,  Jong Kyoung Kim  2 ,  Eunyoung Choi  15  16  23 ,  James R Goldenring  15  16  23  24 ,  Jae-Ho Cheong  25  26  27  28  29  30 ,  Hyunki Kim  31 ,  Daniel E Stange  32  33  34 ,  Heetak Lee  35 ,  Bon-Kyoung Koo  36  37  38 ,  Ji-Hyun Lee  39  40
Affiliations
  • 1. Center for Genome Engineering, Institute for Basic Sciences, Daejeon, Republic of Korea.
  • 2. Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
  • 3. Department of Biology, Kyung Hee University, Seoul, Republic of Korea.
  • 4. Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
  • 5. Department of Medical and Biological Sciences, The Catholic University of Korea, Bucheon, Republic of Korea.
  • 6. National Center for Tumor Diseases Dresden(NCT/UCC), a Partnership Between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carusm, Technische Universität Dresden, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
  • 7. Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
  • 8. Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Vienna, Austria.
  • 9. Vienna BioCenter PhD Program, Doctoral School of the University of Vienna and Medical University of Vienna, Vienna, Austria.
  • 10. Core 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), Dresden, Germany.
  • 11. Graduate School of Stem Cell and Regenerative Biology, KAIST, Daejeon, 34141, Republic of Korea.
  • 12. Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
  • 13. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
  • 14. Department 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.
  • 15. Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 16. Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 17. Precision Medicine Center, Future Innovation Research Division, Seoul National University Bundang Hospital (SNUBH), Seongnam, Gyeonggi-do, 13620, Republic of Korea.
  • 18. Department of Genomic Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, 13620, Republic of Korea.
  • 19. Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Gyeonggi-do, 13620, Republic of Korea.
  • 20. Gradiant Bioconvergence Inc., Seoul, Republic of Korea.
  • 21. Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
  • 22. KAIST Stem Cell Center, KAIST, Daejeon, 34141, Republic of Korea.
  • 23. Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
  • 24. Nashville VA Medical Center, Nashville, TN, USA.
  • 25. Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea. [email protected].
  • 26. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. [email protected].
  • 27. Department 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. [email protected].
  • 28. Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea. [email protected].
  • 29. Chronic Intractable Disease for Systems Medicine Research Center, Yonsei University College of Medicine, Seoul, Republic of Korea. [email protected].
  • 30. Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea. [email protected].
  • 31. Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea. [email protected].
  • 32. Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. [email protected].
  • 33. National Center for Tumor Diseases Dresden(NCT/UCC), a Partnership Between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carusm, Technische Universität Dresden, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany. [email protected].
  • 34. German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Dresden, Germany. [email protected].
  • 35. Center for Genome Engineering, Institute for Basic Sciences, Daejeon, Republic of Korea. [email protected].
  • 36. Center for Genome Engineering, Institute for Basic Sciences, Daejeon, Republic of Korea. [email protected].
  • 37. Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. [email protected].
  • 38. Graduate School of Stem Cell and Regenerative Biology, KAIST, Daejeon, 34141, Republic of Korea. [email protected].
  • 39. Center for Genome Engineering, Institute for Basic Sciences, Daejeon, Republic of Korea. [email protected].
  • 40. Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, Republic of Korea. [email protected].
  • # Contributed equally.
PMID: 41398956 DOI: 10.1186/s12943-025-02543-z
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.

Keywords
Gastric cancer; KRAS–MAPK–WNT7B axis; Tumor microenvironment; WNT self-sufficiency.
Products