Abstract
Cancer is increasingly recognized as a systemic disease, extending beyond local alterations to systemic alterations in distant organs through the release of various factors that promote tumor progression and metastasis. Here, we applied hyperspectral stimulated Raman scattering (hSRS) microscopy to study metabolic alterations in the liver driven by distant tumors, revealing unprecedented accumulation of vitamin A-enriched lipid droplets. Quantitative spectral analysis uncovered increased unsaturation levels and abnormal vitamin A ester. Notably, inhibition of secretory pathways in remote tumors effectively abrogated these metabolic alterations, with FABP5 in tumor-derived extracellular vesicles identified as a key mediator. These findings uncover a unique aspect of cancer progression mechanisms, implicating tumor-driven systemic lipid metabolic remodeling and vitamin A dysregulation in metastatic progression and therapeutic response.
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Data availability
All data required to evaluate the conclusions of this study are included within the paper. The RNA-seq data generated in this study have been deposited in the NCBI Gene Expression Omnibus (GEO) with accession code GSE222707 (liver tissue from mice xenografted with MDA-MB-231 cells and the tumor-free control group). The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (https://proteomecentral.proteomexchange.org) with the dataset identifier PXD069130 (proteome of 231 EV, https://www.iprox.cn/page/PSV023.html;?url=1733464844096CNk4, password: nGs3) and the dataset identifier PXD069253 (proteome of 10 A EV, https://www.iprox.cn/page/PSV023.html;?url=1733464899910oQzg, password: KUWQ). One of the paired measurements for MDA-MB-231 and MCF10A EV in Fig. 5E is supplemented in the Supplementary Data 1 file. The raw mass spectrometry-based proteomic data for Fig. 5A are from the dataset identifier PXD047470. Source data for graphs and charts are supplied as Supplementary Data 1 with this paper. Uncropped and unedited blot/gel images are included in the Supplementary Information file.
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Acknowledgements
The authors thank Dr. Yongqing Zhang for his expert assistance with the SRS imaging system, and Drs. Young-Ho Chung, Hyo-Il Jung, and Seung Il Kim for advising on their previous database. This work was supported by the National Natural Science Foundation of China (82372011), Zhejiang Provincial Natural Science Foundation of China (LZ25H180001), Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0525100/2024ZD0525103), and the Fundamental Research Funds for the Central Universities (226-2025-00034, 2025ZFJH01-01).
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X.H. and H.J.L. designed the study. X.H. performed SRS imaging and analysis. M.L., W.H., and W.Y. designed and performed the animal and RNA-seq experiments. W.H. performed Western blotting and EV characterizations. Y.Z. performed SRS spectral measurement of fatty acids. D.Z. developed and supervised SRS imaging experiments. W.Z. performed cell experiments. X.H. and W.Z. performed bioinformatics analysis. Q.Z. and Y.Z. performed pancreatic cancer animal experiments. X.H. and H.J.L. wrote the manuscript with inputs from all authors.
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Huang, X., Zhou, W., Hou, W. et al. Tumor-secreted factors induce aberrant accumulation of vitamin A–enriched lipid droplets in the liver. Commun Biol (2025). https://doi.org/10.1038/s42003-025-09404-x
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DOI: https://doi.org/10.1038/s42003-025-09404-x
