Prajnamitra Ray Putra, Beh Chaw Yee, Tang Wen-Hung, Ruan Shu-Chian, Cheng Yuan-Yuan, Kuo Pei-Teng, Tien Yu-Wen, Hsieh Patrick Ching-Ho
Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan.
Theranostics. 2025 Jul 2;15(15):7693-7708. doi: 10.7150/thno.108873. eCollection 2025.
The gut microbiota and its metabolites significantly influence cancer development and metastasis. Among these, formate, the simplest short-chain fatty acid (SCFA), remains underexplored in the context of metastasis. This study investigates the role of microbiota-derived formate in exacerbating pulmonary metastasis in melanoma and pancreatic ductal adenocarcinoma (PDAC), aiming to elucidate its mechanistic contributions to cancer progression. Using antibiotics-induced dysbiosis in mice, we quantified plasma formate levels via nuclear magnetic resonance (NMR) metabolomics and identified gut bacterial contributors through 16S rRNA sequencing. Formate's effects on melanoma and PDAC lung metastases were evaluated through supplementation experiments. Cellular assays, metabolomics, and gene expression analyses further elucidated its mechanistic impact. Dysbiosis significantly increased circulating formate levels, with identified as key contributors. Formate supplementation enhanced melanoma and PDAC lung metastases by promoting cancer cell proliferation, migration, and nucleotide synthesis. Mechanistic studies revealed that formate upregulated one-carbon metabolism, critical for tumor aggressiveness, and increased the production of metabolites like glutathione, facilitating oxidative stress resistance. Microbiota-derived formate plays a critical role in enhancing pulmonary metastasis by modulating cancer cell metabolism. These findings highlight the therapeutic potential of targeting formate production or its associated metabolic pathways to mitigate cancer spread. Additionally, microbiome modulation emerges as a promising complementary approach to improving cancer treatment outcomes.
肠道微生物群及其代谢产物对癌症的发展和转移有显著影响。其中，甲酸作为最简单的短链脂肪酸（SCFA），在转移方面的研究仍较少。本研究调查了微生物群衍生的甲酸在加剧黑色素瘤和胰腺导管腺癌（PDAC）肺转移中的作用，旨在阐明其对癌症进展的机制性贡献。通过抗生素诱导小鼠肠道菌群失调，我们利用核磁共振（NMR）代谢组学定量血浆甲酸水平，并通过16S rRNA测序确定肠道细菌来源。通过补充实验评估了甲酸对黑色素瘤和PDAC肺转移的影响。细胞实验、代谢组学和基因表达分析进一步阐明了其机制性影响。肠道菌群失调显著增加了循环甲酸水平， 被确定为关键因素。补充甲酸通过促进癌细胞增殖、迁移和核苷酸合成增强了黑色素瘤和PDAC的肺转移。机制研究表明，甲酸上调了对肿瘤侵袭性至关重要的一碳代谢，并增加了谷胱甘肽等代谢产物的产生，促进了氧化应激抗性。微生物群衍生的甲酸通过调节癌细胞代谢在增强肺转移中起关键作用。这些发现突出了靶向甲酸生成或其相关代谢途径以减轻癌症扩散的治疗潜力。此外，调节微生物群成为改善癌症治疗效果的一种有前景的补充方法。
