Dear Editors,
On behalf of the authors, I would like to submit our manuscript entitled “Integrating bulk RNA-seq and scRNA-seq analyses revealed the function and clinical value of thrombospondin in colon cancer” for publishing on Computational and Structural Biotechnology Journal. All authors have read and approved this final version. We declared that neither the whole nor any part of this paper has been published, accepted or submitted to any other journal. All authors confirmed that they had no conflicts of interest and approved the manuscript.
Due to its invisibility, colon cancer is rarely detected at an early stage and its progression leads to a significantly worse prognosis for patients. Mounting evidence indicates that the extracellular matrix within the tumor microenvironment is constantly undergoing dynamic changes during cancer progression. Matrix proteins play a pivotal role in maintaining extracellular matrix homeostasis and are frequently dysregulated in several types of malignancy. Functioning as a bridge between the extracellular matrix and cells, matrix proteins influence cellular activities involving cancer-associated fibroblasts, monocyte-macrophages, and tumor cells by modifying interactions between cells and the extracellular matrix. Consequently, they perform important functions in anti-tumor immunity and other processes. Owing to their excessive expression and diverse structural domains, matrix proteins have been regarded as promising targets for cancer therapy. Among these, TSP, an matrix glycoprotein, remarkably impacts anti-tumor immunity, angiogenesis, epithelial-mesenchymal transition(EMT) and other processes in a variety of cancer types, including breast, gastric and prostate cancer, but the role of this family in colon cancer and its clinical value is unknown. In this study, We utilized a total of 1981 samples from ten high-throughput datasets (including six bulk RNA-seq datasets, three scRNA-seq datasets and one Spatial transcriptome dataset) to investigate the function and clinical value of the TSP family in colon cancer via survival analysis, unsupervised clustering, functional enrichment, drug sensitivity, and tumor microenvironment-related analyses(eg, Gene Set Enrichment Analysis (GSEA),Gene Set Variation Analysis (GSVA),Immuno-Oncology Biological Research (IOBR),The Tumor Immune Dysfunction and Exclusion (TIDE), spatial localization, monocle2,cellphonedb, etc.).
The major findings of the study are: (a) In cancer, THBS2 and COMP from the TSP family showed significant elevation and held prognostic significance. Moreover, the TSP family demonstrated a significant positive correlation with immune cells and EMT marker genes. (b) Based on TSPs expression, patients can be divided into two clusters with distinct prognoses. TSPs-H group exhibited high immune and stromal cell infiltration, along with elevated T-cell exhaustion. (c) We found that THBS2 and COMP may be associated with the differentiation of CAFs to pan-iCAFs and pan-dCAFs. These two CAFs subtypes possess high matrix remodelling activity; Moreover, THBS2 enhanced CAFs communication with vascular endothelial cells and monocyte-macrophages. THBS2+ CAFs exhibited higher scores in the angiogenic, EMT, Wnt, and TGF-β signaling pathways than THBS2- CAFs, suggesting that THBS2 may be associated with stronger pro-carcinogenic activity of CAFs. Our research combined bulk and scRNA-seq analyses to uncover the impact of the TSP family on the colon cancer and its clinical value, and the outcomes offer a theoretical basis for aiming at the TSP family to postpone colon cancer progression.
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