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<p>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<sup>+</sup>PSCs in ECM remodeling, thus serving as a potential therapeutic target to mitigate PDAC progression in aged patients.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月27日

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  • Wenyuan Shi,
  • Haodong Tang,
  • Siyuan Tan,
  • Lishan Wang,
  • Zeqian Yu,
  • Shan Gao,
  • Jiahua Zhou

摘要

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.