ITGB4-mediated metabolic reprogramming of cancer-associated fibroblasts

• Published in: Oncogene Vol. 39; no. 3; pp. 664 - 676
• Main Authors: Sung, Jin Sol, Kang, Chan Woo, Kang, Suki, Jang, Yeonsue, Chae, Young Chan, Kim, Baek Gil, Cho, Nam Hoon
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16-01-2020; Nature Publishing Group
• Subjects: 14/19; 14/28; 38/1; 42/109; 42/35; 631/67/1347; 631/80/86; 64/60; 82/80; Animals; Apoptosis; Breast - pathology; Breast - surgery; Breast cancer; c-Jun protein; Cancer; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; Cell Biology; Cell Line, Tumor; Cell proliferation; Coculture Techniques; Culture Media, Conditioned; Development and progression; Epithelial-Mesenchymal Transition; Exosomes; Exosomes - metabolism; Female; Fibroblasts; Gene Knockdown Techniques; Glucose metabolism; Glycolysis; Health aspects; Human Genetics; Humans; Integrin beta4 - genetics; Integrin beta4 - metabolism; Integrins; Internal Medicine; Lactic acid; Medicine; Medicine & Public Health; Membrane Proteins - metabolism; Mesenchyme; Mice; Mitophagy; Oncology; Paracrine Communication; Phosphorylation; Primary Cell Culture; Proto-Oncogene Proteins - metabolism; Transcription factors; Triple Negative Breast Neoplasms - pathology; Triple Negative Breast Neoplasms - surgery; Tumor Cells, Cultured; Tumor Suppressor Proteins - metabolism; Xenograft Model Antitumor Assays; United Kingdom; South Korea; Germany
• DOI: 10.1038/s41388-019-1014-0
• EISSN: 1476-5594
• ISSN: 0950-9232

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.