ITGB4-mediated metabolic reprogramming of cancer-associated fibroblasts.

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.
Authors	Jin Sol Sung, Chan Woo Kang, Suki Kang, Yeonsue Jang, Young Chan Chae, Baek Gil Kim, Nam Hoon Cho
Journal	Oncogene (Oncogene) Vol. 39 Issue 3 Pg. 664-676 (01 2020) ISSN: 1476-5594 [Electronic] England
PMID	31534187 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	BNIP3L protein, human Culture Media, Conditioned ITGB4 protein, human Integrin beta4 Membrane Proteins Proto-Oncogene Proteins Tumor Suppressor Proteins
Topics	Animals Breast (pathology, surgery) Cancer-Associated Fibroblasts (metabolism, pathology) Cell Line, Tumor Coculture Techniques Culture Media, Conditioned Epithelial-Mesenchymal Transition Exosomes (metabolism) Female Gene Knockdown Techniques Glycolysis Humans Integrin beta4 (genetics, metabolism) Membrane Proteins (metabolism) Mice Mitophagy Paracrine Communication Primary Cell Culture Proto-Oncogene Proteins (metabolism) Triple Negative Breast Neoplasms (pathology, surgery) Tumor Cells, Cultured Tumor Suppressor Proteins (metabolism) Xenograft Model Antitumor Assays

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