2. Academic Validation
  3. Epithelial WNT secretion drives niche escape of developing gastric cancer

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

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. jhcheong@yuhs.ac.
  • 26 Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. jhcheong@yuhs.ac.
  • 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. jhcheong@yuhs.ac.
  • 28 Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea. jhcheong@yuhs.ac.
  • 29 Chronic Intractable Disease for Systems Medicine Research Center, Yonsei University College of Medicine, Seoul, Republic of Korea. jhcheong@yuhs.ac.
  • 30 Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea. jhcheong@yuhs.ac.
  • 31 Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea. kimhyunki@yuhs.ac.
  • 32 Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. daniel.stange@ukdd.de.
  • 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. daniel.stange@ukdd.de.
  • 34 German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Dresden, Germany. daniel.stange@ukdd.de.
  • 35 Center for Genome Engineering, Institute for Basic Sciences, Daejeon, Republic of Korea. leeheetak@ibs.re.kr.
  • 36 Center for Genome Engineering, Institute for Basic Sciences, Daejeon, Republic of Korea. koobk@ibs.re.kr.
  • 37 Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. koobk@ibs.re.kr.
  • 38 Graduate School of Stem Cell and Regenerative Biology, KAIST, Daejeon, 34141, Republic of Korea. koobk@ibs.re.kr.
  • 39 Center for Genome Engineering, Institute for Basic Sciences, Daejeon, Republic of Korea. ji-hyun.lee@ibs.re.kr.
  • 40 Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, Republic of Korea. ji-hyun.lee@ibs.re.kr.
  • # 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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z