Spatially Resolved Niche and Tumor Microenvironmental Alterations in Gastric Cancer Peritoneal Metastases.

Autor:	Zhao JJ; Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Haematology-Oncology, National University Cancer Institute, Singapore; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore; Department of Medicine, National University Hospital, Singapore., Ong CJ; Department of Sarcoma, Peritoneal and Rare Tumors (SPRinT), Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore; Department of Sarcoma, Peritoneal and Rare Tumors (SPRinT), Division of Surgery and Surgical Oncology, Singapore General Hospital, Singapore; Laboratory of Applied Human Genetics, Division of Medical Sciences, National Cancer Centre Singapore, Singapore; SingHealth Duke-NUS Surgery Academic Clinical Program, Duke-NUS Medical School, Singapore; SingHealth Duke-NUS Oncology Academic Clinical Program, Duke-NUS Medical School, Singapore; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore; Singapore Gastric Cancer Consortium, Singapore, Singapore., Srivastava S; Department of Medicine, National University of Singapore, Singapore., Chia DKA; Department of Surgery, University Surgical Cluster, National University Health System, Singapore., Ma H; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore., Huang K; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore., Sheng T; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore., Ramnarayanan K; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore., Ong X; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore., Tay ST; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore., Hagihara T; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore., Tan ALK; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore., Teo MCC; Department of Sarcoma, Peritoneal and Rare Tumors (SPRinT), Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore; Department of Sarcoma, Peritoneal and Rare Tumors (SPRinT), Division of Surgery and Surgical Oncology, Singapore General Hospital, Singapore., Tan QX; Department of Sarcoma, Peritoneal and Rare Tumors (SPRinT), Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore; Department of Sarcoma, Peritoneal and Rare Tumors (SPRinT), Division of Surgery and Surgical Oncology, Singapore General Hospital, Singapore; Laboratory of Applied Human Genetics, Division of Medical Sciences, National Cancer Centre Singapore, Singapore., Ng G; Department of Sarcoma, Peritoneal and Rare Tumors (SPRinT), Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore; Department of Sarcoma, Peritoneal and Rare Tumors (SPRinT), Division of Surgery and Surgical Oncology, Singapore General Hospital, Singapore; Laboratory of Applied Human Genetics, Division of Medical Sciences, National Cancer Centre Singapore, Singapore., Tan JW; Department of Sarcoma, Peritoneal and Rare Tumors (SPRinT), Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore; Department of Sarcoma, Peritoneal and Rare Tumors (SPRinT), Division of Surgery and Surgical Oncology, Singapore General Hospital, Singapore; Laboratory of Applied Human Genetics, Division of Medical Sciences, National Cancer Centre Singapore, Singapore., Ng MCH; Division of Medical Oncology, National Cancer Centre, Singapore., Gwee YX; Department of Haematology-Oncology, National University Cancer Institute, Singapore., Walsh R; Department of Haematology-Oncology, National University Cancer Institute, Singapore., Law JH; Department of Surgery, University Surgical Cluster, National University Health System, Singapore., Shabbir A; Department of Surgery, University Surgical Cluster, National University Health System, Singapore., Kim G; Department of Surgery, University Surgical Cluster, National University Health System, Singapore., Tay Y; Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Her Z; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore., Leoncini G; Pathology and Laboratory Medicine Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Teh BT; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore., Hong JH; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore., Tay RYK; Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Teo CB; Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Dings MPG; Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands; Oncode Institute, Amsterdam, The Netherlands; Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, The Netherlands., Bijlsma M; Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands; Oncode Institute, Amsterdam, The Netherlands; Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, The Netherlands., Lum JHY; Department of Pathology, National University Hospital, Singapore., Mathur S; Department of General Surgery, Division of Surgery and Surgical Oncology, Singapore General Hospital, Singapore., Pietrantonio F; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Blum SM; Department of Medicine, Division of Hematology-Oncology, Massachusetts General Hospital, Boston, Massachusetts., van Laarhoven H; Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, The Netherlands; Department of Medical Oncology, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands., Klempner SJ; Department of Medicine, Division of Hematology-Oncology, Massachusetts General Hospital, Boston, Massachusetts., Yong WP; Department of Haematology-Oncology, National University Cancer Institute, Singapore; Singapore Gastric Cancer Consortium, Singapore, Singapore; Division of Medical Oncology, National Cancer Centre, Singapore., So JBY; Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Singapore Gastric Cancer Consortium, Singapore, Singapore; Department of Surgery, University Surgical Cluster, National University Health System, Singapore; Division of Surgical Oncology, National University Cancer Institute, Singapore., Chen Q; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore. Electronic address: qchen@imcb.a-star.edu.sg., Tan P; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore; Singapore Gastric Cancer Consortium, Singapore, Singapore; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore; Division of Medical Oncology, National Cancer Centre, Singapore; SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore. Electronic address: gmstanp@duke-nus.edu.sg., Sundar R; Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Haematology-Oncology, National University Cancer Institute, Singapore; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore; Singapore Gastric Cancer Consortium, Singapore, Singapore; The N.1 Institute for Health, National University of Singapore, Singapore. Electronic address: raghav.sundar@yale.edu.
Jazyk:	angličtina
Zdroj:	Gastroenterology [Gastroenterology] 2024 Dec; Vol. 167 (7), pp. 1384-1398.e4. Date of Electronic Publication: 2024 Aug 13.
DOI:	10.1053/j.gastro.2024.08.007
Abstrakt:	Background & Aims: Peritoneal metastasis (PM) in gastric cancer (GC) is associated with poor prognosis and significant morbidity. We sought to understand the genomic, transcriptomic, and tumor microenvironment (TME) features that contribute to peritoneal organotropism in GC. Methods: We conducted a comprehensive multi-omic analysis of 548 samples from 326 patients, including primary tumors, matched normal tissues; peritoneal metastases, and adjacent-normal peritoneal tissues. We used whole exome sequencing, whole transcriptome sequencing, and digital spatial profiling to investigate molecular alterations, gene expression patterns, and TME characteristics associated with PM. Results: Our analysis identified specific genomic alterations in primary tumors, including mutations in ELF3, CDH1, and PIGR, and TME signatures, such as stromal infiltration and M2 macrophage enrichment, associated with increased risk of PM. We observed distinct transcriptional programs and immune compositions in GCPM compared with liver metastases, highlighting the importance of the TME in transcoelomic metastasis. We found differential expression of therapeutic targets between primary tumors and PM, with lower CLDN18.2 and FGFR2b expression in PM. We unravel the roles of the TME in niche reprogramming within the peritoneum, and provide evidence of pre-metastatic niche conditioning even in early GC without clinical PM. These findings were further validated using a humanized mouse model, which demonstrated niche remodeling in the peritoneum during transcoelomic metastasis. Conclusion: Our study provides a comprehensive molecular characterization of GCPM and unveils key biological principles underlying transcoelomic metastasis. The identified predictive markers, therapeutic targets, and TME alterations offer potential avenues for targeted interventions and improved patient outcomes. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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