GDF15 promotes 5-Fluorouracil and Oxaliplatin resistance by promoting stem cell-like phenotype in colorectal cancer

BACKGROUND: Despite recent advances in chemotherapy for colorectal cancer (CRC), chemotherapy-sensitive tumours often develop resistance to treatment, which remains a major clinical challenge. This acquired chemoresistance limits the efficacy of subsequent therapies and is associated with a poor prognosis. Therefore, this study identified the mechanisms of acquired chemoresistance in CRC and developed innovative targeted therapies. METHODS: 5-fluorouracil (5-FU)-and oxaliplatin (OX)-resistant CRC cells were established through long-term exposure to anticancer drugs, and RNA sequencing (RNA-seq) was performed. RNA-seq data integrated analysis from resistant cells and public single-cell RNA-seq datasets from clinical CRC samples was conducted to identify key drivers of chemoresistance. Prognostic significance was evaluated by immunohistochemical analysis of liver metastasis specimens from patients with CRC who underwent curative resection of the primary tumours. RESULTS: Chemotherapy exposure enriched high stemness and activated TGF-β signalling. GDF15 was identified as a key molecule upregulated in both chemoresistant and high-stemness cells. Clinically, high GDF15 expression is associated with early recurrence and poor prognosis. Functional assays demonstrated that GDF15 overexpression promoted chemoresistance, stemness, and migratory capacity of CRC cells. CONCLUSIONS: GDF15 promotes chemoresistance in CRC by promoting stem cell-like properties. These findings provide insights into therapeutic strategies for overcoming acquired chemoresistance and improving outcomes.