ALDH1A3 promotes aggressive basal-like pancreatic cancer through an AP-1/RUNX2 enhancer network
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.
Authors
- Jan Akkan
- Kathleen Schuck (ORCID: https://orcid.org/0009-0003-2769-046X)
- Susanne Raulefs
- Xiaoping Zou (ORCID: https://orcid.org/0000-0003-4147-7051)
- Kuirong Jiang (ORCID: https://orcid.org/0000-0002-2849-5450)
- Jörg Kleeff (ORCID: https://orcid.org/0000-0003-3432-6669)
- Yuan Wan (ORCID: https://orcid.org/0000-0002-0219-5118)
- Bo Kong (ORCID: https://orcid.org/0009-0006-5188-5998)
- Jingxiong Hu
- Lingling Zhang (ORCID: https://orcid.org/0000-0001-5070-8523)
- Xuetian Qian
- Zuguang Gu (ORCID: https://orcid.org/0000-0002-7395-8709)
- Susanne Roth (ORCID: https://orcid.org/0000-0002-5136-4686)
- Lei Wang (ORCID: https://orcid.org/0000-0001-7275-4846)
- Christoph Kahlert (ORCID: https://orcid.org/0000-0003-4124-7918)
- Jing Cao (ORCID: https://orcid.org/0000-0001-9551-5143)
- André L. Mihaljević (ORCID: https://orcid.org/0000-0003-1902-657X)
- Christoph Michalski (ORCID: https://orcid.org/0000-0003-3520-1040)
- Ingrid Herr (ORCID: https://orcid.org/0000-0002-2389-6300)
- Chao Li (ORCID: https://orcid.org/0000-0002-1950-0190)
- Zhiheng Zhang (ORCID: https://orcid.org/0000-0003-4299-5379)
- Yuanyuan Yu (ORCID: https://orcid.org/0000-0001-7945-6833)
- Maggie Haitian Wang (ORCID: https://orcid.org/0000-0003-1223-4595)
- Hongzhen Li (ORCID: https://orcid.org/0000-0001-6393-3009)
- Zipeng Lu
- Qi Zhang (ORCID: https://orcid.org/0000-0002-6096-0690)
- Yifeng Sun (ORCID: https://orcid.org/0000-0001-7561-9367)
- Yanan Niu (ORCID: https://orcid.org/0009-0007-8662-3696)
- Mingyue Hu (ORCID: https://orcid.org/0009-0002-1817-0748)
- Chao Fang (ORCID: https://orcid.org/0000-0003-0005-6939)
- Shanshan Shen (ORCID: https://orcid.org/0009-0000-7889-5674)
- Helmut Friess
- Shuang Nie
- Zhao Shi
- Mengyue Shi
Institutions
- Binghamton University (US)
- Chinese University of Hong Kong (HK)
- Nankai University (CN)
- Heidelberg University (DE)
- Tianjin Medical University General Hospital (CN)
- TUM Klinikum (DE)
- Nanjing Drum Tower Hospital (CN)
- University Children's Hospital Tübingen (DE)
- Jiangsu Province Hospital (CN)
- University Hospital Ulm (DE)
- First Affiliated Hospital Zhejiang University (CN)
- Technical University of Munich (DE)
- Martin Luther University Halle-Wittenberg (DE)
- Nanjing Medical University (CN)
Publication Details
- Journal
- Oncogene
- Published
- 2025-08-08
- DOI
- https://doi.org/10.1038/s41388-025-03530-w
- Citations
- 3
- Primary Topic
- Pancreatic and Hepatic Oncology Research
- Type
- article
- Field-Weighted Citation Impact
- 3.14
Funders
- Wilhelm Sander-Stiftung
- Princess Margaret Cancer Foundation
- Pancreatic Cancer Canada Foundation
- Jiangsu Commission of Health
- Deutsche Forschungsgemeinschaft
- National Natural Science Foundation of China
- Ministry of Education of the People's Republic of China
- Deutsche Krebshilfe
- Nanjing Drum Tower Hospital
- Canadian Cancer Society Research Institute