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ITGB4-mediated metabolic reprogramming of cancer-associated fibroblasts

Oncogene volume 39, pages 664–676 (2020)Cite this article

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Abstract

Integrin beta 4 (ITGB4) overexpression in cancer cells contributes to cancer progression. However, the role of stromal ITGB4 expression in cancer progression remains poorly understood, despite stromal ITGB4 overexpression in malignant cancers. In our study, ITGB4-overexpressing triple negative breast cancer (TNBC) cells provided cancer-associated fibroblasts (CAFs) with ITGB4 proteins via exosomes, which induced BNIP3L-dependent mitophagy and lactate production in CAFs. In coculture assays, the ITGB4-induced mitophagy and glycolysis were suppressed in CAFs by knocking down ITGB4 or inhibiting exosome generation in MDA-MB-231, or blocking c-Jun or AMPK phosphorylation in CAFs. ITGB4-overexpressing CAF-conditioned medium promoted the proliferation, epithelial-to-mesenchymal transition, and invasion of breast cancer cells. In a co-transplant mouse model, MDA-MB-231 made a bigger tumor mass with CAFs than ITGB4 knockdown MDA-MB-231. Herein, we presented how TNBC-derived ITGB4 protein triggers glycolysis in CAFs via BNIP3L-dependent mitophagy and suggested the possibility that ITGB4-induced mitophagy could be targeted as a cancer therapy.

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Acknowledgements

This study was supported by the Mid-Career Researcher Program (no. 2019R1A2B5B01069934; NHC) and Challenges in Creative Research (no. 2019R1I1A1A01060549; BGK) through a National Research Foundation of Korea grant, and The Health Fellowship Foundation grants funded by Yuhan Corporation. The authors thank Medical Illustration & Design, a part of the Medical Research Support Services of Yonsei University College of Medicine, for all artistic support related to this work.

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  1. These authors contributed equally: Baek Gil Kim, Nam Hoon Cho

Authors and Affiliations

  1. Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea

    Jin Sol Sung, Chan Woo Kang, Baek Gil Kim & Nam Hoon Cho

  2. Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea

    Suki Kang, Yeonsue Jang, Baek Gil Kim & Nam Hoon Cho

  3. Severance Biomedical Science Institute (SBSI), Yonsei University College of Medicine, Seoul, South Korea

    Suki Kang & Nam Hoon Cho

  4. School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, South Korea

    Young Chan Chae

  5. Global 5-5-10 System Biology, Yonsei University, Seoul, South Korea

    Nam Hoon Cho

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Sung, J.S., Kang, C.W., Kang, S. et al. ITGB4-mediated metabolic reprogramming of cancer-associated fibroblasts. Oncogene 39, 664–676 (2020). https://doi.org/10.1038/s41388-019-1014-0

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