Abstract
BackgroundCancer-associated fibroblasts (CAFs) contribute notably to colorectal cancer (CRC) tumorigenesis, stiffness, angiogenesis, immunosuppression and metastasis, and could serve as a promising therapeutic target. Our purpose was to construct CAF-related prognostic signature for CRC.MethodsWe performed bioinformatics analysis on single-cell transcriptome data derived from Gene Expression Omnibus (GEO) and identified 208 differentially expressed cell markers from fibroblasts cluster. Bulk gene expression data of CRC was obtained from The Cancer Genome Atlas (TCGA) and GEO databases. Univariate Cox regression and least absolute shrinkage operator (LASSO) analyses were performed on TCGA training cohort (n = 308) for model construction, and was validated in TCGA validation (n = 133), TCGA total (n = 441), GSE39582 (n = 470) and GSE17536 (n = 177) datasets. Microenvironment Cell Populations-counter (MCP-counter) and Estimate the Proportion of Immune and Cancer cells (EPIC) methods were applied to evaluated CAFs infiltrations from bulk gene expression data. Real-time polymerase chain reaction (qPCR) was performed in tissue microarrays containing 80 colon cancer samples to further validate the prognostic value of the CAF model. pRRophetic and Tumor Immune Dysfunction and Exclusion (TIDE) algorithms were utilized to predict chemosensitivity and immunotherapy response. Human Protein Atlas (HPA) databases and immunohistochemistry were used to evaluate the protein expressions.ResultsA nine-gene prognostic CAF-related signature was established in training cohort. Kaplan–Meier survival analyses revealed patients with higher CAF risk scores were correlated with adverse prognosis in each cohort. MCP-counter and EPIC results consistently revealed CAFs infiltrations were significantly higher in high CAF risk group. Patients with higher CAF risk scores were more prone to not respond to immunotherapy, but were more sensitive to several conventional chemotherapeutics, suggesting a potential strategy of combining chemotherapy with anti-CAF therapy to improve the efficacy of current T-cell based immunotherapies. Univariate and multivariate Cox regression analyses verified the CAF model was as an independent prognostic indicator in predicting overall survival, and a CAF-based nomogram was then built for clinical utility in predicting prognosis of CRC.ConclusionTo conclude, the CAF-related signature could serve as a robust prognostic indicator in CRC, which provides novel genomics evidence for anti-CAF immunotherapeutic strategies.
Highlights
Cancer-associated fibroblasts (CAFs) contribute notably to colorectal cancer (CRC) tumorigenesis, stiffness, angiogenesis, immunosuppression and metastasis, and could serve as a promising therapeutic target
Zheng et al Cancer Cell Int (2021) 21:552 analyses verified the CAF model was as an independent prognostic indicator in predicting overall survival, and a CAFbased nomogram was built for clinical utility in predicting prognosis of CRC
After preprocessing scRNA-seq data based on the stringent quality control metrics as noted, 8696 high-quality cell samples isolated from the four discovery CRC tissues were screened and illustrated in Fig. 2a, and a strong positive correlation between numbers of detected genes and sequencing depth was observed with the Pearson’s correlation of 0.94 (Fig. 2b)
Summary
Cancer-associated fibroblasts (CAFs) contribute notably to colorectal cancer (CRC) tumorigenesis, stiffness, angiogenesis, immunosuppression and metastasis, and could serve as a promising therapeutic target. The reciprocal and dynamic interactions between tumor cells and their surrounding TME play crucial roles in CRC tumorigenesis, progression and metastasis, as well as anticancer efficacy and drug resistance [7, 8], and have attracted wide attention in recent years. As the major TME stromal cellular constituents, cancer-associated fibroblasts (CAFs) were found to promote tumorigenesis and enhance the aggressiveness of cancer cells, and to induce chronic inflammation by producing pro-inflammatory cytokines that are responsible for immune tolerance and tumor metastasis [9,10,11,12]. Targeting CAFs along with current tumor cell-targeting agents could be promising therapeutic strategies to synergistically counteract CRC progression
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