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<p>The basal-like transcriptional subtype of pancreatic ductal adenocarcinoma (PDAC) is linked to therapy resistance and poor prognosis. The cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) is a critical enzyme in acetaldehyde metabolism, but the interconnection to the basal-like subtype is poorly understood. Here, we identified ALDH1A3 as a key gene, which correlates with reduced survival and increased tumor growth. Functional studies revealed interaction of ALDH1A3 with genes like FAM3C, MCC, PMEPA1, and IRS2, forming a network driving PDAC progression. Chromatin profiling showed that ALDH1A3 affects acetylation of histone 3, mediating AP-1 activity, particularly via FOS family members, activating oncogenic pathways such as MAPK and TNF signaling. RUNX2 emerged as a therapeutic target within this network, as its knockdown disrupted MAPK signaling and reduced tumor growth. These findings emphasize the role of ALDH1A3 in linking nuclear metabolic-epigenetic programming in basal-like PDAC, highlighting it as a promising therapeutic target for novel treatment strategies.</p>

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ALDH1A3 promotes aggressive basal-like pancreatic cancer through an AP-1/RUNX2 enhancer network

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月8日

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  • Xiaoping Zou,
  • Shuang Nie,
  • Jing Cao,
  • Mengyue Shi,
  • Kathleen Schuck,
  • Zhao Shi,
  • Lingling Zhang,
  • Hongzhen Li,
  • Yifeng Sun,
  • Chao Fang,
  • Jingxiong Hu,
  • Yiqi Niu,
  • Yuanyuan Yu,
  • Zhiheng Zhang,
  • Chao Li,
  • Mingyue Hu,
  • Lei Wang,
  • Kuirong Jiang,
  • Zipeng Lu,
  • Jan Akkan,
  • Susanne Raulefs,
  • Christoph Kahlert,
  • Susanne Roth,
  • Ingrid Herr,
  • Yuan Wan,
  • Andre Mihaljevic,
  • Xuetian Qian,
  • Qi Zhang,
  • Maggie Haitian Wang,
  • Jörg Kleeff,
  • Helmut Friess,
  • Zuguang Gu,
  • Christoph W. Michalski,
  • Shanshan Shen,
  • Bo Kong

摘要

The basal-like transcriptional subtype of pancreatic ductal adenocarcinoma (PDAC) is linked to therapy resistance and poor prognosis. The cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) is a critical enzyme in acetaldehyde metabolism, but the interconnection to the basal-like subtype is poorly understood. Here, we identified ALDH1A3 as a key gene, which correlates with reduced survival and increased tumor growth. Functional studies revealed interaction of ALDH1A3 with genes like FAM3C, MCC, PMEPA1, and IRS2, forming a network driving PDAC progression. Chromatin profiling showed that ALDH1A3 affects acetylation of histone 3, mediating AP-1 activity, particularly via FOS family members, activating oncogenic pathways such as MAPK and TNF signaling. RUNX2 emerged as a therapeutic target within this network, as its knockdown disrupted MAPK signaling and reduced tumor growth. These findings emphasize the role of ALDH1A3 in linking nuclear metabolic-epigenetic programming in basal-like PDAC, highlighting it as a promising therapeutic target for novel treatment strategies.