The tumor-associated fibroblasts regulate urothelial carcinoma progression

Abstract Tumor-associated fibroblasts (CAFs) regulate tumorigenesis, tumor cell proliferation, and metastasis via secreting related regulatory factors; however, the evidence for CAFs in regulating development of upper tract urothelial carcinoma (UTUC) remains unclear. Here, by utilizing single-cell RNA sequencing (scRNA-seq), single-nucleus RNA sequencing (snRNA-seq), SpaTial enhanced resolution omics-sequencing (Stereo-seq), and UTUC immunofluorescence chip cohort to construct the first comprehensive microenvironmental atlas of CAFs, we investigated the roles of CAFs in UTUC progression. Through hierarchical clustering and the copy number variation (CNV) scores of UTUC epithelial cells, we first classified tumor epithelial cells into high-malignant, medium-malignant, and low-malignant potential categories. We found that the myofibroblastic CAFs1 (myCAFs1) and myCAFs2 subclusters exhibited significant interaction signals with all three types of epithelial cells, among which high-malignant epithelial cells (HMECs) exhibited pronounced communication signals with CAFs, and FN1 and COL1A1 generated by CAFs played critical roles in this process, suggesting that the progression of UTUC may be attributed to the activation of tumor cells by CAFs. Both myCAFs1 and myCAFs2 simultaneously affect bladder urothelial carcinoma (BUC) prognosis, with the risk model showing good consistency across cohorts. The study constructs a multi-omics landscape of UTUC and identify common prognostic markers shared with BUC.