Extracellular matrix sensing regulates intratumoral heterogeneity of autophagic flux

Autophagy, a programmed self-eating process, underlies the progression of multifactorial diseases like pancreatic ductal adenocarcinoma (PDA). Except for nutrient availability, the contribution of microenvironmental factors to autophagy regulation is not well understood. Through integrating functional genomics and tumor-like 3D cultures, we show that human PDA cells regulate their autophagy levels by sensing the extracellular matrix (ECM) via the integrinα3-Hippo-YAP1 axis. The spatial proximity of PDA cells to the ECM shapes their intracellular autophagy levels, leading to heterogeneous biological responses. Specifically, PDA cells with low autophagy levels are proliferative, whereas those with high autophagy levels display better tolerance to chemotherapies. Targeting the ECM-mediated autophagy regulation reduces autophagic heterogeneity, alters PDA growth, and shapes antitumor responses to FDA-approved therapies. In summary, we have characterized a non-metabolic regulation of autophagy through ECM sensing, opening the possibility to investigate and target ECM-specific outputs in diseases.