Bidirectional crosstalk between cancer cells and cancer-associated fibroblasts in mixed organoid system elicits transcriptomic characteristics of pancreatic cancer with potential therapeutic vulnerabilities [RNA-seq]
Pancreatic cancer's aggressiveness and poor response to conventional treatment have long necessitated a personalized medicine platform. Patient-derived pancreatic cancer organoids (PCOs) with matching genetic mutations have emerged as valuable tools for drug screening. However, PCOs, composed solely of cancer cells, may exhibit different characteristics from the original tumors due to the absence of the tumor microenvironment (TME). To address these issues, we extensively characterized the transcriptomic features of matched patient-derived mixed PCO-CAF systems, combining pancreatic cancer cells and cancer-associated fibroblasts (CAFs), compared to PCOs and the original tumors. The mixed PCO-CAF model closely resembled the patient tissue's transcriptomic traits, indicating its potential in reflecting the TME. Single-cell RNA sequencing revealed different cell populations in the mixed PCO-CAF system, including myofibroblast-like CAFs and inflammatory CAFs, influencing the essential features of cancer cells in the TME. Several growth factors and cytokines were identified in both the patient tissue and mixed PCO-CAFs, suggesting the importance of intercellular signaling communication. Importantly, disrupting these interactions could lead to antitumor responses. Given the cumulative implications of our dataset, the mixed PCO-CAF emerges as a clinically applicable paradigm for personalized therapeutics. Overall design: Total RNAs from five corresponding sets of patient tumor tissue, patient-derived PCO, and mixed PCO-CAF were isolated.