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Gut, Nov 23 2024, gutjnl-2024-332901 | https://doi.org/10.1136/gutjnl-2024-332901
Spatial dissection of tumour microenvironments in gastric cancers reveals the immunosuppressive crosstalk between CCL2+ fibroblasts and STAT3-activated macrophages
Sung Hak Lee,1,† Dagyeong Lee,2,† Junyong Choi,2,3 Hye Jeong Oh,2 In-Hye Ham,2,4 Daeun Ryu,5 Seo-Yeong Lee,5,6 Dong-Jin Han,5,6 Sunmin Kim,5,6 Youngbeen Moon,5,6 In-Hye Song,7 Kyo Young Song,8 Hyeseong Lee,1 Seungho Lee,9 Hoon Hur,2,3,4,* Tae-Min Kim 5,10,11,*
1Department of Hospital Pathology, Seoul St. Mary’s Hostpital, Collage of Medicine, The Catholic University of Korea, Seoul, The Republic of Korea
2Department of Surgery, Ajou University School of Medicine, Suwon, The Republic of Korea
3Cancer Biology Graduate Program, Ajou University School of Medicine, Suwon, The Republic of Korea
4Inflamm-Aging Translational Research Center, Ajou University School of Medicine, Suwon, The Republic of Korea
5Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, The Republic of Korea
6Department of Biomedicine & Health Sciences, Graduate School, The Catholic University of Korea, Seoul, The Republic of Korea
7Department of Pathology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, The Republic of Korea
8Division of Gastrointestinal Surgery, Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, The Republic of Korea
9Department of Surgery, Yonsei University, Seoul, The Republic of Korea
10Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, The Republic of Korea
11CMC Institute for Basic Medical Science, the Catholic Medical Center of The Catholic University of Korea, Seoul, The Republic of Korea
2Department of Surgery, Ajou University School of Medicine, Suwon, The Republic of Korea
3Cancer Biology Graduate Program, Ajou University School of Medicine, Suwon, The Republic of Korea
4Inflamm-Aging Translational Research Center, Ajou University School of Medicine, Suwon, The Republic of Korea
5Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, The Republic of Korea
6Department of Biomedicine & Health Sciences, Graduate School, The Catholic University of Korea, Seoul, The Republic of Korea
7Department of Pathology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, The Republic of Korea
8Division of Gastrointestinal Surgery, Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, The Republic of Korea
9Department of Surgery, Yonsei University, Seoul, The Republic of Korea
10Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, The Republic of Korea
11CMC Institute for Basic Medical Science, the Catholic Medical Center of The Catholic University of Korea, Seoul, The Republic of Korea
†SHL and DL are joint first authors.
*Corresponding authors: correspondence to Hoon Hur or Tae-Min Kim
Abstract
Background A spatially resolved, niche-level analysis of tumour microenvironments (TME) can provide insights into cellular interactions and their functional impacts in gastric cancers (GC).
Objective Our goal was to translate the spatial organisation of GC ecosystems into a functional landscape of cellular interactions involving malignant, stromal and immune cells.
Design We performed spatial transcriptomics on nine primary GC samples using the Visium platform to delineate the transcriptional landscape and dynamics of malignant, stromal and immune cells within the GC tissue architecture, highlighting cellular crosstalks and their functional consequences in the TME.
Results GC spatial transcriptomes with substantial cellular heterogeneity were delineated into six regional compartments. Specifically, the fibroblast-enriched TME upregulates epithelial-to-mesenchymal transformation and immunosuppressive response in malignant and TME cells, respectively. Cell type-specific transcriptional dynamics revealed that malignant and endothelial cells promote the cellular proliferations of TME cells, whereas the fibroblasts and immune cells are associated with procancer and anticancer immunity, respectively. Ligand-receptor analysis revealed that CCL2-expressing fibroblasts promote the tumour progression via JAK-STAT3 signalling and inflammatory response in tumour-infiltrated macrophages. CCL2+ fibroblasts and STAT3-activated macrophages are co-localised and their co-abundance was associated with unfavourable prognosis. We experimentally validated that CCL2+ fibroblasts recruit myeloid cells and stimulate STAT3 activation in recruited macrophages. The development of immunosuppressive TME by CCL2+ fibroblasts were also validated in syngeneic mouse models.
Conclusion GC spatial transcriptomes revealed functional cellular crosstalk involving multiple cell types among which the interaction between CCL2+ fibroblasts and STAT3-activated macrophages plays roles in establishing immune-suppressive GC TME with potential clinical relevance.
Objective Our goal was to translate the spatial organisation of GC ecosystems into a functional landscape of cellular interactions involving malignant, stromal and immune cells.
Design We performed spatial transcriptomics on nine primary GC samples using the Visium platform to delineate the transcriptional landscape and dynamics of malignant, stromal and immune cells within the GC tissue architecture, highlighting cellular crosstalks and their functional consequences in the TME.
Results GC spatial transcriptomes with substantial cellular heterogeneity were delineated into six regional compartments. Specifically, the fibroblast-enriched TME upregulates epithelial-to-mesenchymal transformation and immunosuppressive response in malignant and TME cells, respectively. Cell type-specific transcriptional dynamics revealed that malignant and endothelial cells promote the cellular proliferations of TME cells, whereas the fibroblasts and immune cells are associated with procancer and anticancer immunity, respectively. Ligand-receptor analysis revealed that CCL2-expressing fibroblasts promote the tumour progression via JAK-STAT3 signalling and inflammatory response in tumour-infiltrated macrophages. CCL2+ fibroblasts and STAT3-activated macrophages are co-localised and their co-abundance was associated with unfavourable prognosis. We experimentally validated that CCL2+ fibroblasts recruit myeloid cells and stimulate STAT3 activation in recruited macrophages. The development of immunosuppressive TME by CCL2+ fibroblasts were also validated in syngeneic mouse models.
Conclusion GC spatial transcriptomes revealed functional cellular crosstalk involving multiple cell types among which the interaction between CCL2+ fibroblasts and STAT3-activated macrophages plays roles in establishing immune-suppressive GC TME with potential clinical relevance.
논문정보
- Research article
- 2024년 11월 (BRIC 등록일 2024-11-25)
- 국내 연구진
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