ITGB4-mediated metabolic reprogramming of cancer-associated fibroblasts

Jin Sol Sung, Chan Woo Kang, Suki Kang, Yeonsue Jang, Young Chan Chae, Baek Gil Kim, Nam Hoon Cho

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)664-676
Number of pages13
JournalOncogene
Volume39
Issue number3
DOIs
Publication statusPublished - 2020 Jan 16

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Sung, J. S., Kang, C. W., Kang, S., Jang, Y., Chae, Y. C., Kim, B. G., & Cho, N. H. (2020). ITGB4-mediated metabolic reprogramming of cancer-associated fibroblasts. Oncogene, 39(3), 664-676. https://doi.org/10.1038/s41388-019-1014-0