Integrating bulk RNA-seq and scRNA-seq analyses revealed the function and clinical value of thrombospondins in colon cancer

作者全名：Li, Jing; Tang, Ying; Long, Fei; Tian, Luyao; Tang, Ao; Ding, Lihui; Chen, Juan; Liu, Mingwei

作者地址：[Li, Jing; Tang, Ying; Tian, Luyao; Tang, Ao; Ding, Lihui; Chen, Juan; Liu, Mingwei] Chongqing Med Univ, Coll Lab Med, Key Lab Clin Lab Diagnost, Chongqing 400046, Peoples R China; [Tang, Ying] Peoples Hosp Qingbaijiang Dist, Med Lab, Chengdu 61300, Peoples R China; [Long, Fei] Wuhan Univ, Dept Lab Med, Zhongnan Hosp, Wuhan, Peoples R China; [Long, Fei] Wuhan Univ, Ctr Single Cell Om & Tumor Liquid Biopsy, Zhongnan Hosp, Wuhan, Peoples R China

通信作者：Chen, J; Liu, MW (通讯作者)，Chongqing Med Univ, Coll Lab Med, Key Lab Clin Lab Diagnost, Chongqing 400046, Peoples R China.

来源：COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001246468200001

JCR分区：Q2

影响因子：4.4

年份：2024

卷号：23

期号：　

开始页：2251

结束页：2266

文献类型：Article

关键词：Colon Cancer; Thrombospondins; Tumor microenvironment; THBS2; Cancer-associated fibroblasts

摘要：Background: Acting as mediators in cell-matrix and cell-cell communication, matricellular proteins play a crucial role in cancer progression. Thrombospondins (TSPs), a type of matricellular glycoproteins, are key regulators in cancer biology with multifaceted roles. Although TSPs have been implicated in anti-tumor immunity and epithelial-mesenchymal transition (EMT) in several malignancies, their specific roles to colon cancer remain elusive. Addressing this knowledge gap is essential, as understanding the function of TSPs in colon cancer could identify new therapeutic targets and prognostic markers. Methods: Analyzing 1981 samples from 10 high-throughput datasets, including six bulk RNA-seq, three scRNAseq, and one spatial transcriptome dataset, our study investigated the prognostic relevance, risk stratification value, immune heterogeneity, and cellular origin of TSPs, as well as their influence on cancer-associated fibroblasts (CAFs). Utilizing survival analysis, unsupervised clustering, and functional enrichment, along with multiple correlation analyses of the tumor-microenvironment (TME) via Gene Set Variation Analysis (GSVA), spatial localization, Monocle2, and CellPhoneDB, we provided insights into the clinical and cellular implications of TSPs. Results: First, we observed significant upregulation of THBS2 and COMP in colon cancer, both of which displayed significant prognostic value. Additionally, we detected a significant positive correlation between TSPs and immune cells, as well as marker genes of EMT. Second, based on TSPs expression, patients were divided into two clusters with distinct prognoses: the high TSPs expression group (TSPs-H) was characterized by pronounced immune and stromal cell infiltration, and notably elevated T-cell exhaustion scores. Subsequently, we found that THBS2 and COMP may be associated with the differentiation of CAFs into pan-iCAFs and pan-dCAFs, which are known for their heightened matrix remodeling activities. Moreover, THBS2 enhanced CAFs communication with vascular endothelial cells and monocyte-macrophages. CAFs expressing THBS2 ( THBS2 + CAFs) demonstrated higher scores across multiple signaling pathways, including angiogenic, EMT, Hedgehog, Notch, Wnt, and TGF- beta, when compared to THBS2 - CAFs. These observations suggest that THBS2 may be associated with stronger procarcinogenic activity in CAFs. Conclusions: This study revealed the crucial role of TSPs and the significant correlation between THBS2 and CAFs interactions in colon cancer progression, providing valuable insights for targeting TSPs to mitigate cancer progression.

基金机构：Science and Technology Research Plan Project of Chongqing Education Commission [KJQN202100418]; Natural Science Foundation of Chongqing [cstc2021jcyj-msxm0317]; National Natural Science Foundation of China [82203591]; Medical Science Foundation of the Chengdu Municipal Health Commission [2022299]

基金资助正文：This study was supported by the Science and Technology Research Plan Project of Chongqing Education Commission (KJQN202100418) , the Natural Science Foundation of Chongqing (No.cstc2021jcyj-msxm0317) , the National Natural Science Foundation of China (No.82203591) , the Medical Science Foundation of the Chengdu Municipal Health Commission (No.2022299) .