Inflammatory memory inactivates AMPK-stimulated DDR1 degradation to enable pancreatic cancer growth.

Inflammation and stromal remodeling control pancreatic ductal adenocarcinoma (PDAC), but whether and how these cues are integrated at the molecular level remains unclear. Here, we identify a metabolic checkpoint that controls the stability of the collagen receptor discoidin domain receptor 1 (DDR1), and subsequent tumorigenesis. Defective Col-I remodeling deprives PDAC cells of the high-affinity DDR1 ligand, the ¾Col-I fragment, resulting in reduced cellular adenosine triphosphate (ATP) and activation of adenosine monophosphate-activated protein kinase (AMPK). AMPK phosphorylates DDR1 at T519, promoting its recognition by the E3 ubiquitin ligase adaptor FBXW2 and subsequent proteasomal degradation. Importantly, this degradation pathway can be disabled by inflammatory signals. Exposure to inflammatory cytokines induces methylation-dependent silencing of FBXW2, establishing an inflammatory memory that preserves DDR1 stability, enabling sustained ligand-triggered receptor oligomerization and downstream NF-κB-NRF2 signaling even in PDAC restrictive stromal environments. Together, these findings identify regulated receptor turnover as a mechanism through which stromal architecture, metabolic state, and inflammatory memory are integrated to control PDAC progression.