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

## TL;DR

This study shows that methylmalonic acid (MMA) in older people promotes changes in the pancreas that worsen pancreatic cancer progression.

## Contribution

The study identifies MMA-induced LOXL2+ PSCs as a novel mechanism linking aging and ECM changes to PDAC progression.

## Key findings

- Elevated MMA levels in aged PDAC patients correlate with increased linear ECM alignment in normal pancreatic tissues.
- MMA promotes LOXL2 expression in PSCs via the KLF10/SP1 transcriptional complex, enhancing ECM alignment and tumor progression.
- Increased linear ECM alignment in aged patients is linked to more advanced tumor stages and worse outcomes.

## Abstract

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).

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).