TRIB1 regulates tumor growth via controlling tumor-associated macrophage phenotypes and is associated with breast cancer survival and treatment response
Molecular mechanisms that regulate tumor-associated macrophage (TAM) phenotype and function are incompletely understood. The pseudokinase TRIB1 has been reported as a regulator of macrophage phenotypes, both in mouse and human systems.
Methods: Bioinformatic analysis was used to investigate the link between TRIB1 expression in breast cancer and therapeutic response to chemotherapy. In vivo models of breast cancer included immune-competent mice to characterize the consequences of altered (reduced or elevated) myeloid Trib1 expression on tumor growth and composition of stromal immune cell populations. Results: TRIB1 was highly expressed by TAMs in breast cancer and high TRIB1 expression correlated with response to chemotherapy and patient survival. Both overexpression and knockout of myeloid Trib1 promote mouse breast tumor growth, albeit through different molecular mechanisms. Myeloid Trib1 deficiency led to an early acceleration of tumor growth, paired with a selective reduction in perivascular macrophage numbers in vivo and enhanced oncogenic cytokine expression in vitro. In contrast, elevated levels of Trib1 in myeloid cells led to an increased late-stage mammary tumor volume, coupled with a reduction of NOS2 expressing macrophages and an overall reduction of macrophages in hypoxic tumor regions. In addition, we show that myeloid Trib1 is a previously unknown, negative regulator of the anti-tumor cytokine IL-15, and that increased myeloid Trib1 expression leads to reduced IL-15 levels in mammary tumors, with a consequent reduction in the number of T-cells that are key to anti-tumor immune responses.
Conclusions: Together, these results define a key role for TRIB1 in chemotherapy responses for human breast cancer and provide a mechanistic understanding for the importance of the control of myeloid TRIB1 expression in the development of this disease.
This study was supported by grants from the European Union’s Horizon 2020 Marie SkłodowskaCurie Innovative Training Network, TRAIN (project no. 721532). The work was supported extensively by the University of Sheffield Biological Services Team and Fiona Wright in the Histology Facility. CARDIOGENICS was funded by the European Union FP6 program (LSHM-CT-2006-037593). We would like to thank Dr Yang Li and Dr Benjamin Durham for recruitment of blood from healthy participants Dr Victoria Ridger for overseeing human ethics. We thank Dr Penelope Ottowell for providing the breast cancer cells, and Dr Haider Al-Janabi for providing mammary tumor tissues developed in C57BL/6. S.C-L was supported by a MINECO/FEDER research grant (RTI2018-094130-B-100). MM was supported by Cancer Research UK (grant reference: C25574/A24321) and by the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska Curie grant agreement No 777682 (CANCER). EKT was a member and supported by the UK Coronavirus Immunology Consortium (UK-CIC, MR/V028448/1).
CitationKim, T., Johnston, J., Castillo-Lluva, S., Cimas, F. J., Hamby, S., Cardiogenics Consortium*, Gonzalez-Moreno, S., Villarejo-Campos, P., Goodall, A. H., Velasco, G., Ocana, A., Muthana, M., & Kiss-Toth, E. (2022). TRIB1 regulates tumor growth via controlling tumor-associated macrophage phenotypes and is associated with breast cancer survival and treatment response. Theranostics, 12(8), 3584–3600. https://doi.org/10.7150/thno.72192
Author affiliationDepartment of Cardiovascular Sciences and Leicester NIHR Biomedical Research Centre
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