Single-cell programmed cell death regulator patterns guide intercellular communication of cancer-associated fibroblasts that contribute to colorectal cancer progression.

BACKGROUND: The significance of programmed cell death (PCD) in the context of cancer development and progression is widely acknowledged, yet its specific impact on cancer-associated fibroblasts (CAFs) remains a topic of ongoing investigation. Therefore, the study aims to explore the role of PCD in regulating CAFs and its potential implications for CRC progression. METHODS: CAFs from single-cell data of 23 colorectal cancer (CRC) patients were clustered by non-negative matrix factorization (NMF) and the impact of these subpopulations on the prognosis of CRC patients was predicted using public database cohorts. RESULTS: In total, we screened eight PCDs that are associated with significant prognostic impacts for CRC patients, and based on PCD regulators, we defined multiple subpopulations of CAFs associated with PCDs. Additionally, we found that the PCD key regulators may be closely related to the clinical and biological characteristics of CRC and the pseudotime trajectory of major CAFs subpopulations. Bulk RNA sequencing analyses revealed that subpopulations of CAFs mediated by PCD hold prognostic value for CRC patients. CellChat analysis further illustrated the extensive interactions between PCD-associated CAFs subpopulations and tumor epithelial cells. Following Cox regression and survival analyses, it was determined that the paraptosis-mediated CAFs subpopulation had the most pronounced impact on CRC patient prognosis, with DDIT3 identified as a marker protein influencing patient outcomes. CONCLUSIONS: Our study reveals for the first time how PCD-mediated communication between CAFs regulates tumor growth in CRC patients and influences their prognosis, and has identified that DDIT3(+) CAFs associated with paraptosis exhibit the most pronounced influence on the prognosis of individuals with CRC.