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Enhanced epithelial-mesenchymal transition signatures are linked with adverse tumor microenvironment, angiogenesis and worse survival in gastric cancer

Cancer Gene Therapy (2024)Cite this article

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Abstract

Epithelial-mesenchymal transition (EMT) is a crucial mechanism that facilitates cancer cell metastasis. Despite its importance, the clinical significance of EMT in gastric cancer (GC) patients has yet to be clearly demonstrated. For gauging the extent of EMT in GC, we employed gene set variation analysis to score 807 patient samples from two large cohorts: TCGA and GSE84437. In both cohorts, EMT high GC showed a significant association with worse overall survival (hazard ratio (HR) = 1.74, p = 0.011 and HR = 2.01, p < 0.001, respectively). This association was stronger when considering the EMT signature score compared to the individual expressions of EMT-related genes (CDH1, CDH2, VIM, and FN1). While the EMT signature level did not differ among various cancers, high EMT signature specifically correlated with survival in GC alone. Mucinous and diffuse histological types exhibited higher EMT levels compared to others (p < 0.001), and the EMT signature level was correlated with tumor depth and AJCC stage (all p < 0.001). Interestingly, the EMT score was an independent factor for overall and disease-specific survival (multivariate; p = 0.006 and 0.032, respectively). EMT high GC displayed a lower fraction of Th1 cells and a higher fraction of dendritic cells, M1 macrophages and several stromal cells. EMT high GC exhibited an inverse correlation with cell proliferation-related gene sets. While they significantly enriched multiple pro-cancerous gene sets, such as TGF-β signaling, hypoxia, and angiogenesis. The presence of EMT signature in a bulk tumor was linked to TGF-β signaling, hypoxia, and angiogenesis, and was also associated with poorer survival outcomes in GC patients.

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Fig. 1: Association of the EMT score with patient survival in gastric cancer in the TCGA and GSE84437 cohorts.
Fig. 2: Association of enhanced EMT signature with patient survival among several cancers.
Fig. 3: EMT score and clinicopathological features of gastric cancer.
Fig. 4: Association of the EMT signature with immunity in gastric cancer.
Fig. 5: The association of EMT signature with mutation- and cell proliferation-related factors in gastric cancer.
Fig. 6: The association of EMT signature level with angiogenesis in gastric cancer in the cohorts: TCGA and GSE84437.

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Data availability

All the cohorts/datasets used in this study; The Cancer Genome Atlas (TCGA) and GSE84437 are all publicly available without any restrictions via cBioportal or Gene Expression Omnibus (GEO).

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Funding

This research was supported by the National Institutes of Health, USA grant number R37CA248018, R01CA250412, R01CA251545, R01EB029596, as well as US Department of Defense BCRP grant number W81XWH-19-1-0674 and W81XWH-19-1-0111 to K.T., and Yokohama Foundation for Advancement of Medical Science to M.O. National Cancer Institute, cancer center support grant P30CA016056 supports Roswell Park Comprehensive Cancer Center.

Author information

Authors and Affiliations

  1. Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan

    Masanori Oshi, Sachika Kinoshita, Yuko Tamura, Takashi Kosaka, Hirotoshi Akiyama, Chikara Kunisaki, Kazuaki Takabe & Itaru Endo

  2. Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA

    Masanori Oshi & Kazuaki Takabe

  3. Department of Medical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA

    Arya Mariam Roy

  4. Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA

    Li Yan

  5. Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY, 14263, USA

    Kazuaki Takabe

  6. Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan

    Kazuaki Takabe

  7. Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, 160-8402, Japan

    Kazuaki Takabe

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Contributions

Conceptualization, IE, KN, KT, MO, TC, TI; Methodology, KT, MA, MO, RW, SK; Formal Analysis, MO; Writing-original draft preparation, MO; Writing-review and editing, A.M.R., A.Y., K.T., L.Y.; Supervision, K.T.; Project administration, K.T.

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Correspondence to Masanori Oshi.

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Oshi, M., Roy, A.M., Yan, L. et al. Enhanced epithelial-mesenchymal transition signatures are linked with adverse tumor microenvironment, angiogenesis and worse survival in gastric cancer. Cancer Gene Ther (2024). https://doi.org/10.1038/s41417-024-00756-w

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