The MondoA-dependent TXNIP/GDF15 axis predicts oxaliplatin response in colorectal adenocarcinomas.
Jinhai DengTeng PanDan WangYourae HongZaoqu LiuXingang ZhouZhengwen AnLifeng LiGiovanna AlfanoGang LiLuigi DolcettiRachel EvansJose M VicencioPetra VlckovaYue ChenJames MonypennyCamila Araujo De Carvalho GomesGregory WeitsmanKenrick NgCaitlin McCarthyXiaoping YangZedong HuJoanna C PorterChristopher J TapeMingzhu YinFengxiang WeiManuel Rodriguez-JustoJin ZhangSabine TejparRichard Esmond BeatsonTony T NgPublished in: EMBO molecular medicine (2024)
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.
Keyphrases
- regulatory t cells
- nlrp inflammasome
- chemotherapy induced
- prognostic factors
- oxidative stress
- immune response
- healthcare
- dendritic cells
- diabetic rats
- squamous cell carcinoma
- locally advanced
- squamous cell
- palliative care
- high glucose
- single cell
- genome wide
- quality improvement
- type diabetes
- toll like receptor
- radiation therapy
- skeletal muscle
- drug induced
- binding protein
- metabolic syndrome
- climate change
- heat stress
- human health
- affordable care act
- label free
- childhood cancer