Starved epithelial cells uptake extracellular matrix for survival

Area of Science:

• Cell Biology
• Molecular Biology
• Cancer Research

Background:

• Epithelial cell survival depends on extracellular matrix (ECM) adhesion for nutrient uptake and metabolism.
• Oncogene activation can override ECM adhesion requirements.
• PI3K/mTOR pathway inhibition induces apoptosis in matrix-detached cells, but not matrix-attached cells, suggesting alternative survival mechanisms in the latter.

Purpose of the Study:

• To investigate the mechanisms by which matrix-attached cells maintain nutrient supply under conditions of reduced PI3K/mTOR signaling.
• To identify potential therapeutic targets for PI3K/mTOR-resistant cancers.

Main Methods:

• Studied human mammary epithelial cells and fibroblasts under dietary restriction or growth factor starvation.
• Analyzed the expression and internalization of β4-integrin and laminin.
• Investigated the localization of internalized laminin and its effect on intracellular amino acid levels and mTORC1 signaling.
• Assessed the role of fibroblast-secreted matrix proteins in epithelial cell survival.

Main Results:

• Matrix-attached human mammary epithelial cells upregulate and internalize β4-integrin and laminin during starvation.
• Endocytosed laminin is trafficked to lysosomes, increasing intracellular essential amino acids and enhancing mTORC1 signaling, thereby preventing cell death.
• Starved human fibroblasts secrete matrix proteins that support starved epithelial cell growth, dependent on epithelial β4-integrin expression.

Conclusions:

• A novel crosstalk mechanism exists between stromal fibroblasts and epithelial cells during starvation, mediated by ECM components and β4-integrin.
• This pathway allows matrix-attached cells to bypass PI3K/mTOR inhibition and maintain survival.
• Targeting this fibroblast-epithelial cell crosstalk could be a therapeutic strategy for PI3K/mTOR-resistant tumors.