MMA-induced LOXL2+ PSCs promote linear ECM alignment in the aging pancreas leading to pancreatic cancer progression.

Pancreatic ductal adenocarcinoma (PDAC) is an age-associated malignancy closely linked to the extracellular matrix (ECM). However, the impact of age-related ECM changes in the normal pancreas on PDAC progression remains unclear. Here, we find that increased linear ECM alignment in normal pancreatic tissues from aged PDAC patients is associated with PDAC progression and worse outcomes. Furthermore, serum methylmalonic acid (MMA) levels are elevated in aged PDAC patients and associated with increased linear ECM alignment in normal pancreatic tissues of PDAC patients. Functionally, MMA promotes LOXL2 expression in pancreatic stellate cells (PSCs), increases linear ECM alignment in normal pancreatic tissues, and facilitates tumor progression. Mechanistically, MMA upregulates KLF10, which forms a transcriptional complex with SP1 to enhance LOXL2 expression in PSCs. Our study demonstrates the role of MMA-induced LOXL2⁺PSCs in ECM remodeling, thus serving as a potential therapeutic target to mitigate PDAC progression in aged patients. Schematic diagram showing the molecular mechanism by which MMA-induced LOXL⁺PSCs promote PDAC progression in the aging pancreas. In aged individuals, elevated levels of MMA in the blood induce the activation of the KLF10/SP1‒LOXL2 axis in PSCs to increase linear ECM alignment. Following the initiation of pancreatic cancer, this increased linear ECM alignment leads to increased tumor invasion into surrounding tissues, resulting in a greater proportion of stage T3/T4 tumors and a greater incidence of LVI and PNI in aged patients, ultimately leading to poorer outcomes (This schematic was created with www.figdraw.com ,export id: PRPRS4e268).