Single-cell RNA sequencing highlights the role of inflammatory cancer-associated fibroblasts in bladder urothelial carcinoma

Abstract

Although substantial progress has been made in cancer biology and treatment, clinical outcomes of bladder carcinoma (BC) patients are still not satisfactory. The tumor microenvironment (TME) is a potential target. Here, by single-cell RNA sequencing on 8 BC tumor samples and 3 para tumor samples, we identify 19 different cell types in the BC microenvironment, indicating high intra-tumoral heterogeneity. We find that tumor cells down regulated MHC-II molecules, suggesting that the downregulated immunogenicity of cancer cells may contribute to the formation of an immunosuppressive microenvironment. We also find that monocytes undergo M2 polarization in the tumor region and differentiate. Furthermore, the LAMP3 + DC subgroup may be able to recruit regulatory T cells, potentially taking part in the formation of an immunosuppressive TME. Through correlation analysis using public datasets containing over 3000 BC samples, we identify a role for inflammatory cancer-associated fibroblasts (iCAFs) in tumor progression, which is significantly related to poor prognosis. Additionally, we characterize a regulatory network depending on iCAFs. These results could help elucidate the protumor mechanisms of iCAFs. Our results provide deep insight into cancer immunology and provide an essential resource for drug discovery in the future.

Overexpressed pseudogene MT1L associated with tumor immune infiltrates and indicates a worse prognosis in BLCA

“…In particular, BLCA is characterized by marked infiltration by immune cells such as Tregs and MDSCs [33,34]. Tregs and MDSCs are vital regulators of antitumor responses in BLCA, and the intratumoral presence of these cells is correlated with the poor clinical outcome that has already been established [35][36][37]. Tregs act as a vital immunosuppressive factor to promote tumor [38].…”

Single-cell analysis reveals the pan-cancer invasiveness-associated transition of adipose-derived stromal cells into COL11A1-expressing cancer-associated fibroblasts

“…There are several published results, often conflicting with each other, identifying various distinct subtypes of fibroblasts, resulting from computational clustering methods following dimensionality reduction, or using particular marker genes (such as αSMA , which, interestingly we found that is not consistently expressed in the COL11A1 -expressing CAFs, therefore it should not be used as its marker), which represent an approximation of biological reality. Examples include the hC1 and hC0 clusters in [47], the C9 and C10 clusters in [39], the CAF2 and CAF1 clusters in [33], the iCAF and myCAF clusters in [48,49] and the iCAF an mCAF clusters in [50]. A review of such results in pancreatic cancer appears in [51].…”

“…As an example of conflicting results, the “iCAFs” identified in [50] are identical to the normal ASCs (fig. 3b of [50]) as evidenced by the list of its differentially expressed genes ( PTGDS , LUM , CFD , FBLN1 , APOD , DCN , CXCL14 , SFRP2 , MMP2 , all of which appear in Table 5, further validating the ASC signature. Therefore, this identified cluster contains mainly normal cells at the origin of the transition, which should not even be called CAFs.…”

Underlying mechanisms and drug intervention strategies for the tumour microenvironment

“…Moreover, CAFs can also secrete vascular endothelial growth factor (VEGF) to support angiogenesis [ 26 ]. Cancer inflammation-related fibroblasts in bladder cancer produce VEGF, including VEGFA and VEGFB, which bind to VEGF receptors (FLT1, KDR, MET and FLT4) on endothelial cells, promote angiogenesis, affect the proliferation of cancer cells and stromal cells, and may recruit immune cells into the cancer stage [ 27 ].…”