A combined analysis of bulk and single-cell sequencing data reveals that depleted extracellular matrix and enhanced immune processes co-contribute to fluorouracil beneficial responses in gastric cancer

Dong, Shaowei1,2,3; Zhang, Siyu4; Zhao, Pan4; Lin, Guanchuan5,6; Ma, Xiaoshi1; Xu, Jing1; Zhang, Hao7; Hu, Jiliang1,8; Zou, Chang1,3

2022-09-15

10.3389/fimmu.2022.999551

Frontiers in Immunology   Impact Factor & Quartile

1664-3224

Fluorouracil, also known as 5-FU, is one of the most commonly used chemotherapy drugs in the treatment of advanced gastric cancer (GC). Whereas, the presence of innate or acquired resistance largely limits its survival benefit in GC patients. Although accumulated studies have demonstrated the involvement of tumor microenvironments (TMEs) in chemo-resistance induction, so far little is known about the relevance of GC TMEs in 5-FU resistance. To this end, in this study, we investigated the relationship between TME features and 5-FU responses in GC patients using a combined analysis involving both bulk sequencing data from the TCGA database and single-cell RNA sequencing data from the GEO database. We found that depleted extracellular matrix (ECM) components such as capillary/stroma cells and enhanced immune processes such as increased number of M1 polarized macrophages/Memory T cells/Natural Killer T cells/B cells and decreased number of regulatory T cells are two important features relating to 5-FU beneficial responses in GC patients, especially in diffuse-type patients. We further validated these two features in the tumor tissues of 5-FU-benefit GC patients using immunofluorescence staining experiments. Based on this finding, we also established a Pro (63 genes) and Con (199 genes) gene cohort that could predict 5-FU responses in GC with an AUC (area under curve) score of 0.90 in diffuse-type GC patients, and further proved the partial applicability of this gene panel pan-cancer-wide. Moreover, we identified possible communications mediated by heparanase and galectin-1 which could regulate ECM remodeling and tumor immune microenvironment (TIME) reshaping. Altogether, these findings deciphered the relationship between GC TMEs and 5-FU resistance for the first time, as well as provided potential therapeutic targets and predicting rationale to overcome this chemo-resistance, which could shed some light on developing novel precision treatment strategies in clinical practice.

fluorouracil response gastric cancer tumor microenvironments extracellular matrix immune components

SCI

English

First ; Corresponding

[32000465] ; [2021T140276] ; [2020B1515120032] ; [2019B1515120033] ; [JCYJ20210324115800001] ; [2021A1515010919]

Immunology

Immunology

WOS:000862108400001

FRONTIERS MEDIA SA

Web of Science

1.Jinan Univ, Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Clin Med Coll 2,Affiliated Hosp 1, Shenzhen, Peoples R China
2.Jinan Univ, Integrated Chinese & Western Med Postdoctoral Res, Guangzhou, Peoples R China
3.Chinese Univ Hong Kong Shenzhen, Sch Med Life & Hlth Sci, Shenzhen, Peoples R China
4.Southern Univ Sci & Technol, Affiliated Hosp 1, Sch Med, Shenzhen, Peoples R China
5.Southern Med Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Guangzhou, Peoples R China
6.Southern Med Univ, Guangdong Prov Key Lab Single Cell Technol & Appli, Guangzhou, Peoples R China
7.Jinan Univ Med Coll, Inst Precis Canc Med & Pathol, Guangzhou, Peoples R China
8.Guangdong Engn Technol Res Ctr Nervous Anat & Rela, Shenzhen, Peoples R China

Dong, Shaowei,Zhang, Siyu,Zhao, Pan,et al. A combined analysis of bulk and single-cell sequencing data reveals that depleted extracellular matrix and enhanced immune processes co-contribute to fluorouracil beneficial responses in gastric cancer[J]. Frontiers in Immunology,2022,13.

Dong, Shaowei.,Zhang, Siyu.,Zhao, Pan.,Lin, Guanchuan.,Ma, Xiaoshi.,...&Zou, Chang.(2022).A combined analysis of bulk and single-cell sequencing data reveals that depleted extracellular matrix and enhanced immune processes co-contribute to fluorouracil beneficial responses in gastric cancer.Frontiers in Immunology,13.

Dong, Shaowei,et al."A combined analysis of bulk and single-cell sequencing data reveals that depleted extracellular matrix and enhanced immune processes co-contribute to fluorouracil beneficial responses in gastric cancer".Frontiers in Immunology 13(2022).