Starved epithelial cells uptake extracellular matrix for survival

• Published in: Nature communications Vol. 8; no. 1; p. 13989
• Main Authors: Muranen, Taru, Iwanicki, Marcin P, Curry, Natasha L, Hwang, Julie, DuBois, Cory D, Coloff, Jonathan L, Hitchcock, Daniel S, Clish, Clary B, Brugge, Joan S, Kalaany, Nada Y
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 10.01.2017; Nature Portfolio
• Subjects: Adipose Tissue - cytology; Adipose Tissue - metabolism; Animals; Apoptosis; Breast cancer; Cell death; Cell Line; Cell Survival - physiology; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - physiology; Extracellular matrix; Extracellular Matrix - metabolism; Female; Fibroblasts - metabolism; Growth factors; Humans; Integrin beta4 - genetics; Integrin beta4 - metabolism; Kinases; Laminin - metabolism; Laminin - pharmacology; Localization; Mechanistic Target of Rapamycin Complex 1 - metabolism; Medical research; Mice, Inbred Strains; Ovarian cancer; Phosphatidylinositol 3-Kinases - metabolism; Proteins; Starvation; Tumors; United States > US; Massachusetts
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms13989

Extracellular matrix adhesion is required for normal epithelial cell survival, nutrient uptake and metabolism. This requirement can be overcome by oncogene activation. Interestingly, inhibition of PI3K/mTOR leads to apoptosis of matrix-detached, but not matrix-attached cancer cells, suggesting that matrix-attached cells use alternate mechanisms to maintain nutrient supplies. Here we demonstrate that under conditions of dietary restriction or growth factor starvation, where PI3K/mTOR signalling is decreased, matrix-attached human mammary epithelial cells upregulate and internalize β4-integrin along with its matrix substrate, laminin. Endocytosed laminin localizes to lysosomes, results in increased intracellular levels of essential amino acids and enhanced mTORC1 signalling, preventing cell death. Moreover, we show that starved human fibroblasts secrete matrix proteins that maintain the growth of starved mammary epithelial cells contingent upon epithelial cell β4-integrin expression. Our study identifies a crosstalk between stromal fibroblasts and epithelial cells under starvation that could be exploited therapeutically to target tumours resistant to PI3K/mTOR inhibition.