Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Division of Endocrinology, Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
Nat Commun. 2017 Jan 10;8:13989. 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.
细胞外基质黏附对于正常上皮细胞的存活、营养物质摄取和代谢是必需的。这种需求可以通过癌基因的激活来克服。有趣的是，PI3K/mTOR 的抑制会导致基质脱离的癌细胞凋亡，而不是基质附着的癌细胞凋亡，这表明基质附着的细胞使用替代机制来维持营养供应。在这里，我们证明在饮食限制或生长因子饥饿的条件下，PI3K/mTOR 信号通路降低时，基质附着的人乳腺上皮细胞上调并内化β4 整联蛋白及其基质底物层粘连蛋白。内吞的层粘连蛋白定位于溶酶体，导致必需氨基酸的细胞内水平增加，并增强 mTORC1 信号，从而防止细胞死亡。此外，我们还表明，饥饿的成纤维细胞分泌基质蛋白，这些基质蛋白维持饥饿的乳腺上皮细胞的生长，这取决于上皮细胞β4 整联蛋白的表达。我们的研究确定了在饥饿条件下基质成纤维细胞和上皮细胞之间的串扰，这可能在治疗上被利用来靶向对 PI3K/mTOR 抑制有抗性的肿瘤。
