Exploring the role of tumor stemness and the potential of stemness-related risk model in the prognosis of intrahepatic cholangiocarcinoma.

Tumor stem cells (TSCs) have been widely reported to play a critical role in tumor progression and metastasis. We explored the role of tumor stemness in intrahepatic cholangiocarcinoma (iCCA) and established a prognostic risk model related to tumor stemness for prognosis prediction and clinical treatment guidance in iCCA patients. The expression profiles of iCCA samples (E-MTAB-6389 and GSE107943 cohorts) were used in the study. One-class logistic regression algorithm calculated the mRNA stemness index (mRNAsi). The mRNAsi-related genes were used as a basis for the identification of mRNAsi-related molecular subtypes through consensus clustering. The immune characteristics and biological pathways of different subtypes were assessed. The mRNAsi-related risk model was constructed with differentially expressed genes (DEGs) between subtypes. The patients with high mRNAsi had longer overall survival than that with low mRNAsi. Two subtypes were identified with that C2 had higher mRNAsi and better prognosis than C1. Tumor-related pathways such as TGF-β and epithelial-mesenchymal transition (EMT) were activated in C1. C1 had higher enrichment of cancer-associated fibroblasts and tumor-associated macrophages, as well as higher immune response and angiogenesis score than C2. We screened a total 98 prognostic DEGs between C1 and C2. Based on the prognostic DEGs, we constructed a risk model containing three genes (, , and ) that could divide iCCA samples into high- and low-risk groups. The two groups had distinct prognosis and immune characteristics. Notably, the risk score was negatively associated with mRNAsi (R = -0.53). High-risk group had higher enrichment score of T cell inflamed GEP, INF-γ, and cytolytic activity, and lower score of estimated IC50 of 5-fluorouracil and cisplatin than low-risk group. This study clarified the important role of tumor stemness in iCCA and developed an mRNAsi-related risk model for predicting the prognosis and supporting the clinical treatment in iCCA patients. The three genes (, , and ) may serve as potential targets for iCCA treatment.