Cancer-Associated Fibroblasts Affect Tumor Metabolism and Immune Microenvironment in Gastric Cancer and...

Cancer-associated fibroblasts (CAFs) have reported widely involved in cancer progression. However, its underlying mechanism in gastric cancer is still not clarified.

The data used in this study were all downloaded from the Cancer Genome Atlas database. R software and the R packages were used for all the analyses.

In our study, we first quantified the CAFs infiltration using the ssGSEA algorithm. The clinical correlation result showed that CAFs were associated with a worse prognosis and clinical features. Pathway enrichment also indicated several oncogenic pathways in GC patients with high CAFs infiltration, including epithelial-mesenchymal transition (EMT), myogenesis, allograft rejection, the inflammatory response, and IL2/STAT5 signaling. Furthermore, FNDC1 and RSPO3 were identified as the characteristic genes of CAFs through two machine learning algorithms, LASSO logistic regression and SVM-RFE. The following analysis showed that FNDC1 and RSPO3 were associated with more progressive clinical features and had a good prediction efficiency of the CAFs infiltration status in GC patients. Pathway enrichment and genomic instability were performed to explore the underlying mechanisms of FNDC1 and RSPO3. Immune infiltration analysis showed that CAFs were positively correlated with M2 macrophages. Moreover, we found that the GC patients with low CAFs infiltration were more sensitive to immunotherapy. Also, the CAFs, FNDC1, and RSPO3 could generate a certain effect on the sensitivity of doxorubicin, mitomycin, and paclitaxel.

In summary, our study comprehensively investigated the role of CAFs in GC, which might be associated with immunotherapy sensitivity. Meanwhile, FNDC1 and RSPO3 were identified as the underlying targets of GC.