title: Starved epithelial cells uptake extracellular matrix for survival.
abstract: 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.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Taru
authors.initials: T
authors.lastname: Muranen
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Marcin P
authors.initials: MP
authors.lastname: Iwanicki
authors.affiliation: Division of Endocrinology, Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Natasha L
authors.initials: NL
authors.lastname: Curry
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Hwang
authors.affiliation: Division of Endocrinology, Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Cory D
authors.initials: CD
authors.lastname: DuBois
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Coloff
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Hitchcock
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Clary B
authors.identifier: 0000-0001-8259-9245
authors.initials: CB
authors.lastname: Clish
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Joan S
authors.initials: JS
authors.lastname: Brugge
authors.affiliation: Division of Endocrinology, Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Nada Y
authors.identifier: 0000-0001-7489-1035
authors.initials: NY
authors.lastname: Kalaany
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D039663:Integrin beta4 / Q000235:genetics / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism* / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D008815:Mice, Inbred Strains; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D013217:Starvation
chemical_list: C059834:ITGB4 protein, human; D039663:Integrin beta4; D007797:Laminin; D019869:Phosphatidylinositol 3-Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1