PDAC_CSC

Pancreatic cancer is a highly aggressive malignancy and poses significant therapeutic challenges due to resistance to conventional therapies. Cancer stem cells (CSCs) act as key contributors to this resistance with their self-renewal capacity. In this study, we identified the ARPC1B+ CSC subpopulation specifically resistant to gemcitabine through integrated analysis of scRNA-seq and bulk RNA-seq data from pancreatic cancer samples. Additionally, ARPC1B expression was significantly elevated in gemcitabine-resistant CSCs and correlated with higher mutation burden and intra-tumor heterogeneity. Molecular docking analysis identified CK-636 as a potential ARPC1B-targeting agent with high affinity. Ex vivo and in vivo experiments demonstrated that combinational therapy of gemcitabine along with CK-636 could significantly inhibit tumor growth compared to gemcitabine alone, indicating that targeting ARPC1B+ CSCs can sensitize pancreatic cancer to gemcitabine treatment. These findings highlight ARPC1B+ CSCs as a promising therapeutic target for overcoming gemcitabine resistance in pancreatic cancer.Notes: We collected six scRNA-seq datasets of pancreatic ductal adenocarcinoma (PDAC), including GSE263733, GSE197177, GSE212966, GSE155698, GSE141017, and GSE154778. These datasets comprise 15 adjacent normal tissue samples, 58 primary tumors, 16 liver metastases, and 20 peripheral blood mononuclear cell (PBMC) samples. PDACs displayed intratumoral heterogeneity, categorized into 11 clusters based on marker genes. Clusters C1 and C6 were identified as cancer stem cell-like clusters and showed a strong correlation with gemcitabine resistance scores.