Spatially Resolved Niche and Tumor Microenvironmental Alterations in Gastric Cancer Peritoneal Metastases
Year: 2024
Type: article
Study design: Observational Study
Abstract: 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.
Source: Gastroenterology
Authors: Joseph J. Zhao, Chin-Ann Johnny Ong, Supriya Srivastava, Daryl Kai Ann Chia, Haoran Ma, Kiekyon Huang, Taotao Sheng, Kalpana Ramnarayanan, Xuewen Ong, Su Ting Tay, Takeshi Hagihara, Angie Lay Keng Tan, Melissa Ching Ching Teo, Qiu Xuan Tan, Gillian Ng, Joey Wee-Shan Tan, Matthew Chau Hsien Ng, Yong Xiang Gwee, Robert Walsh, Jia Hao Law, Asim Shabbir, Guowei Kim, Yvonne Tay, Zhisheng Her, Giuseppe Leoncini, Bin Tean Teh, Jing Han Hong, Ryan Yong Kiat Tay, Chong Boon Teo, Mark P.G. Dings, Maarten Bijlsma, Jeffrey Huey Yew Lum, Sachin Mathur, Filippo Pietrantonio, Steven M. Blum, Hanneke van Laarhoven, Samuel J. Klempner, Wei Peng Yong, Jimmy Bok Yan So, Qingfeng Chen, Patrick Tan, Raghav Sundar
Institutions: National University of Singapore, National University Cancer Institute, Singapore, Duke-NUS Medical School, National University Hospital, SingHealth, Singapore General Hospital, SingHealth Duke-NUS Academic Medical Centre, National Cancer Centre Singapore, Institute of Molecular and Cell Biology, National University Health System, Agency for Science, Technology and Research, Genome Institute of Singapore, Cancer Science Institute of Singapore, Fondazione IRCCS Istituto Nazionale dei Tumori, Amsterdam UMC Location University of Amsterdam, Cancer Center Amsterdam, Massachusetts General Hospital, National Heart Centre Singapore
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,180
OpenAlex ID: W4401528487