ITGB4-mediated metabolic reprogramming of cancer-associated fibroblasts

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Title
ITGB4-mediated metabolic reprogramming of cancer-associated fibroblasts
Author
Sung, Jin SolKang, Chan WooKang, SukiJang, YeonsueChae, Young ChanKim, Baek GilCho, Nam Hoon
Issue Date
2020-01
Publisher
Nature Publishing Group
Citation
ONCOGENE, v.39, pp.664 - 676
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.
URI
https://scholarworks.unist.ac.kr/handle/201301/30359
URL
https://www.nature.com/articles/s41388-019-1014-0
DOI
10.1038/s41388-019-1014-0
ISSN
0950-9232
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