Oncogenes and Tumor Suppressors Matrix Stiffening and b1 Integrin Drive Subtype- Specific Fibroblast Accumulation in Lung Cancer

The crucial role of tumor-associated fibroblasts (TAF) in cancer progression is now clear in non–small cell lung cancer (NSCLC). However, therapies against TAFs are limited due to a lack of understanding in the subtype-specific mechanisms underlying their accumulation. Here, the mechanical (i.e., matrix rigidity) and soluble mitogenic cues that drive the accumulation of TAFs from major NSCLC subtypes: adenocarcinoma (ADC) and squa-mous cell carcinoma (SCC) were dissected. Fibroblasts were cul-tured on substrata engineered to exhibit normal- or tumor-like stiffnesses at different serum concentrations, and critical regulatory processes were elucidated. In control fibroblasts from nonmalig-nant tissue, matrix stiffening alone increased fibroblast accumu-lation, and this mechanical effect was dominant or comparable with that of soluble growth factors up to 0.5 % serum. The stim