1. The MondoA-dependent TXNIP/GDF15 axis predicts oxaliplatin response in colorectal adenocarcinomas.
- Author
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Deng J, Pan T, Wang D, Hong Y, Liu Z, Zhou X, An Z, Li L, Alfano G, Li G, Dolcetti L, Evans R, Vicencio JM, Vlckova P, Chen Y, Monypenny J, Gomes CAC, Weitsman G, Ng K, McCarthy C, Yang X, Hu Z, Porter JC, Tape CJ, Yin M, Wei F, Rodriguez-Justo M, Zhang J, Tejpar S, Beatson R, and Ng T
- Subjects
- Humans, Antineoplastic Agents therapeutic use, Antineoplastic Agents pharmacology, T-Lymphocytes, Regulatory drug effects, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Oxaliplatin pharmacology, Oxaliplatin therapeutic use, Colorectal Neoplasms drug therapy, Colorectal Neoplasms metabolism, Growth Differentiation Factor 15 metabolism, Growth Differentiation Factor 15 genetics, Carrier Proteins metabolism, Adenocarcinoma drug therapy, Adenocarcinoma metabolism
- Abstract
Chemotherapy, the standard of care treatment for cancer patients with advanced disease, has been increasingly recognized to activate host immune responses to produce durable outcomes. Here, in colorectal adenocarcinoma (CRC) we identify oxaliplatin-induced Thioredoxin-Interacting Protein (TXNIP), a MondoA-dependent tumor suppressor gene, as a negative regulator of Growth/Differentiation Factor 15 (GDF15). GDF15 is a negative prognostic factor in CRC and promotes the differentiation of regulatory T cells (Tregs), which inhibit CD8 T-cell activation. Intriguingly, multiple models including patient-derived tumor organoids demonstrate that the loss of TXNIP and GDF15 responsiveness to oxaliplatin is associated with advanced disease or chemotherapeutic resistance, with transcriptomic or proteomic GDF15/TXNIP ratios showing potential as a prognostic biomarker. These findings illustrate a potentially common pathway where chemotherapy-induced epithelial oxidative stress drives local immune remodeling for patient benefit, with disruption of this pathway seen in refractory or advanced cases., (© 2024. The Author(s).)
- Published
- 2024
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