Matrix Stiffness-Sensitive LDHA Drives Autophagy of Pancreatic Ductal Adenocarcinoma via Lactate-Induced FOXO3 Expression and Lactylation

Autophagy, as a key process of PDAC, significantly accelerates malignant progression and ultimately leads to adverse prognosis. Consequently, it is crucial to comprehend the underlying mechanisms of the interplay between matrix stiffness and PDAC autophagy.

To serve the intent, Polyacrylamide (PA) hydrogels with adjustable stiffness were utilized to cultivate MIA PaCa-2 and PANC-1 cells. The outcomes established that high stiffness induced lactate production via the activation of lactate dehydrogenase A (LDHA), resulting in the upregulation of transcription factor FOXO3 and subsequent induction of autophagy. Interestingly, in vivo experiments, the MIA PaCa-2 cells educated by stiff PA hydrogels exhibited not only higher tumorigenicity, but also persistent phenotype maintenance and gene expression, which implied the potential epigenetic modulation of matrix stiffness.