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ALDH1A3 promotes the lung metastatic organotropism of pancreatic ductal adenocarcinoma through semaphorin signaling

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by early metastasis and poor prognosis. Here, we demonstrate that aldehyde dehydrogenase 1A3 (ALDH1A3) regulates PDAC lung tropism through an epigenetic-axon guidance axis. RNA sequencing analysis of clinical samples r...

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Autores principales: Shen, Shanshan (Autor) , Qian, Xuetian (Autor) , Shi, Zhao (Autor) , Wu, Yuting (Autor) , Zhou, Zitong (Autor) , Nie, Shuang (Autor) , Yu, Yuanyuan (Autor) , Zhou, Siqi (Autor) , Liu, Kun (Autor) , Zhou, Quan (Autor) , Tang, Dehua (Autor) , Lv, Ying (Autor) , Wang, Lei (Autor) , Kong, Bo (Autor) , Li, Hongzhen (Autor) , Zou, Xiaoping (Autor)
Formato: Article (Journal)
Lenguaje:inglés
Publicado: May 21, 2026
In: iScience
Year: 2026, Volumen: 29, Número: 6, Pages: 1-14
ISSN:2589-0042
DOI:10.1016/j.isci.2026.115950
Acceso en línea:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.isci.2026.115950
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S2589004226013258
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Notas de Autor:Shanshan Shen, Xuetian Qian, Zhao Shi, Yuting Wu, Zitong Zhou, Shuang Nie, Yuanyuan Yu, Siqi Zhou, Kun Liu, Quan Zhou, Dehua Tang, Ying Lv, Lei Wang, Bo Kong, Hongzhen Li, and Xiaoping Zou
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Sumario:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by early metastasis and poor prognosis. Here, we demonstrate that aldehyde dehydrogenase 1A3 (ALDH1A3) regulates PDAC lung tropism through an epigenetic-axon guidance axis. RNA sequencing analysis of clinical samples revealed that PDAC lung recurrence is associated with basal-like features and involves retinol metabolism and axon guidance pathways. Mechanistically, ALDH1A3 promotes acetyl-CoA production, enhancing histone H3 (H3K9/K14) acetylation at promoters of axon guidance receptors PLXNB1 and NRP1 to activate their transcription. Consequently, PDAC cells become sensitized to ligands SEMA4D and SEMA3A, which are abundantly expressed in lung epithelial cells. The resulting SEMA4D-PLXNB1 and SEMA3A-NRP1 signaling axes drive early metastatic colonization in the lung. Our findings reveal a regulatory circuit underlying PDAC organotropism and suggest potential therapeutic strategies against metastasis.
Notas:Gesehen am 10.09.2026
Descripción Física:Online Resource
ISSN:2589-0042
DOI:10.1016/j.isci.2026.115950

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