The MondoA-dependent TXNIP/GDF15 1 axis predicts oxaliplatin response in colorectal adenocarcinomas.: Oxaliplatin-induced immunogenicity through the regulation of the TXNIP/GDF15 axis

Jinhai Deng; Teng Pan; Dan Wang; Yourae Hong; Zaoqu  Liu; Xingang Zhou; Zhengwen An; Lifeng Li; Giovanna Alfano; Gang Li; Luigi Dolcetti; Rachel Evans; Jose Vicencio Bustamante; Petra Vlckova; Yue Chen; James Monypenny of Pitmilly; Camila Araujo De Carvalho Gomes; Gregory Weitsman; Kenrick Ng; Caitlin McCarthy; Xiaoping Yang; Zedong Hu; Joanna C. Porter; Christopher J Tape; Mingzhu Yin; Fengxiang  Wei; Manuel Rodriguez-Justo; Jin  Zhang; Sabine Tejpar; Richard Beatson; Tony Ng

The MondoA-dependent TXNIP/GDF15 1 axis predicts oxaliplatin response in colorectal adenocarcinomas. Oxaliplatin-induced immunogenicity through the regulation of the TXNIP/GDF15 axis

Jinhai Deng, Teng Pan, Dan Wang, Yourae Hong, Zaoqu Liu, Xingang Zhou, Zhengwen An, Lifeng Li, Giovanna Alfano, Gang Li, Luigi Dolcetti, Rachel Evans, Jose Vicencio Bustamante, Petra Vlckova, Yue Chen, James Monypenny of Pitmilly, Camila Araujo De Carvalho Gomes, Gregory Weitsman, Kenrick Ng, Caitlin McCarthyXiaoping Yang, Zedong Hu, Joanna C. Porter, Christopher J Tape, Mingzhu Yin, Fengxiang Wei, Manuel Rodriguez-Justo, Jin Zhang, Sabine Tejpar, Richard Beatson, Tony Ng

Research output: Contribution to journal › Article › peer-review

Abstract

Chemotherapy, the standard of care treatment for cancer patients with advanced disease, has been increasingly recognised 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 remodelling for patient benefit, with disruption of this pathway seen in refractory or advanced cases.

Original language	English
Journal	EMBO Molecular Medicine
Publication status	Accepted/In press - 3 Jul 2024

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https://www.embopress.org/doi/full/10.1038/s44321-024-00105-2Licence: CC BY

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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 Bustamante, J., Vlckova, P., Chen, Y., Monypenny of Pitmilly, J., Araujo De Carvalho Gomes, C., Weitsman, G., Ng, K., ... Ng, T. (Accepted/In press). The MondoA-dependent TXNIP/GDF15 1 axis predicts oxaliplatin response in colorectal adenocarcinomas. Oxaliplatin-induced immunogenicity through the regulation of the TXNIP/GDF15 axis. EMBO Molecular Medicine. https://www.embopress.org/doi/full/10.1038/s44321-024-00105-2

@article{f8039c0ffb1f41f6a5d3bfc95ed697c7,

title = "The MondoA-dependent TXNIP/GDF15 1 axis predicts oxaliplatin response in colorectal adenocarcinomas.: Oxaliplatin-induced immunogenicity through the regulation of the TXNIP/GDF15 axis",

abstract = "Chemotherapy, the standard of care treatment for cancer patients with advanced disease, has been increasingly recognised 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 remodelling for patient benefit, with disruption of this pathway seen in refractory or advanced cases.",

author = "Jinhai Deng and Teng Pan and Dan Wang and Yourae Hong and Zaoqu Liu and Xingang Zhou and Zhengwen An and Lifeng Li and Giovanna Alfano and Gang Li and Luigi Dolcetti and Rachel Evans and {Vicencio Bustamante}, Jose and Petra Vlckova and Yue Chen and {Monypenny of Pitmilly}, James and {Araujo De Carvalho Gomes}, Camila and Gregory Weitsman and Kenrick Ng and Caitlin McCarthy and Xiaoping Yang and Zedong Hu and Porter, {Joanna C.} and Tape, {Christopher J} and Mingzhu Yin and Fengxiang Wei and Manuel Rodriguez-Justo and Jin Zhang and Sabine Tejpar and Richard Beatson and Tony Ng",

year = "2024",

month = jul,

day = "3",

language = "English",

journal = "EMBO Molecular Medicine",

issn = "1757-4684",

publisher = "Wiley-Blackwell",

}

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 Bustamante, J, Vlckova, P, Chen, Y, Monypenny of Pitmilly, J , Araujo De Carvalho Gomes, C , 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 & Ng, T 2024, 'The MondoA-dependent TXNIP/GDF15 1 axis predicts oxaliplatin response in colorectal adenocarcinomas. Oxaliplatin-induced immunogenicity through the regulation of the TXNIP/GDF15 axis', EMBO Molecular Medicine. <https://www.embopress.org/doi/full/10.1038/s44321-024-00105-2>

TY - JOUR

T1 - The MondoA-dependent TXNIP/GDF15 1 axis predicts oxaliplatin response in colorectal adenocarcinomas.

T2 - Oxaliplatin-induced immunogenicity through the regulation of the TXNIP/GDF15 axis

AU - Deng, Jinhai

AU - Pan, Teng

AU - Wang, Dan

AU - Hong, Yourae

AU - Liu, Zaoqu

AU - Zhou, Xingang

AU - An, Zhengwen

AU - Li, Lifeng

AU - Alfano, Giovanna

AU - Li, Gang

AU - Dolcetti, Luigi

AU - Evans, Rachel

AU - Vicencio Bustamante, Jose

AU - Vlckova, Petra

AU - Chen, Yue

AU - Monypenny of Pitmilly, James

AU - Araujo De Carvalho Gomes, Camila

AU - Weitsman, Gregory

AU - Ng, Kenrick

AU - McCarthy, Caitlin

AU - Yang, Xiaoping

AU - Hu, Zedong

AU - Porter, Joanna C.

AU - Tape, Christopher J

AU - Yin, Mingzhu

AU - Wei, Fengxiang

AU - Rodriguez-Justo, Manuel

AU - Zhang, Jin

AU - Tejpar, Sabine

AU - Beatson, Richard

AU - Ng, Tony

PY - 2024/7/3

Y1 - 2024/7/3

N2 - Chemotherapy, the standard of care treatment for cancer patients with advanced disease, has been increasingly recognised 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 remodelling for patient benefit, with disruption of this pathway seen in refractory or advanced cases.

AB - Chemotherapy, the standard of care treatment for cancer patients with advanced disease, has been increasingly recognised 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 remodelling for patient benefit, with disruption of this pathway seen in refractory or advanced cases.

M3 - Article

SN - 1757-4684

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

ER -

The MondoA-dependent TXNIP/GDF15 1 axis predicts oxaliplatin response in colorectal adenocarcinomas. Oxaliplatin-induced immunogenicity through the regulation of the TXNIP/GDF15 axis

Abstract

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