Compression-induced metabolic adaptation drives confined tumor cell migration and distant metastasis via malate-dependent microtubule reinforcement.

AbstactMetastasis, responsible for > 90% of cancer-related mortality, represents the most lethal yet least mechanistically understood phase of cancer progression. A critical bottleneck is tumor cell migration through physically confined environments, including dense extracellular matrix, narrow capillaries and endothelial gaps. Although tumor cells reprogram their metabolism to facilitate cancer progression, it remains unclear how specific metabolic adaptations enable them to overcome the unique physical challenges posed by these confined spaces, thereby promoting distant metastasis. We conducted a CRISPR screen targeting 1685 metabolic enzymes and identified dihydrolipoamide dehydrogenase (DLD), a mitochondrial enzyme involved in energy metabolism, as essential for confined migration of tumor cells. Depletion or pharmacological inhibition of DLD suppressed CRC metastasis by impairing tumor cell migration through capillaries and endothelial gaps. Upon mechanical compression, heterogeneous nuclear ribonucleoprotein A0 (hnRNPA0) binds to the adenylate uridylate-rich element (ARE) in the 3′UTR of DLD, enhancing its mRNA stability and upregulating DLD expression in tumor cells during confined migration. Elevated DLD expression enhances tricarboxylic acid (TCA) cycle metabolism, increasing malate levels. Malate interacts with tubulin alpha-1B chain (TUBA1B) to promote microtubule assembly, facilitating confined migration and metastasis. Knock-in of an ARE-deleted DLD mutant (DLD ΔARE) or disruption of the malate–TUBA1B interaction significantly suppressed tumor metastasis. In CRC patients, DLD expression was upregulated in tumor cells within capillaries of primary tumors and correlated with metastatic recurrence. Our findings reveal that compressive forces drive metastatic dissemination by epigenetically reprogramming mitochondrial metabolism, which in turn fuels cytoskeletal remodeling.

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Fig. 1: DLD is required for tumor cell migration in confined spaces and ultimate distant metastasis.Fig. 2: Pharmacological inhibition of DLD dampens tumor metastasis.Fig. 3: DLD mRNA is stabilized upon compression in confined cells.Fig. 4: HnRNPA0 interacts with DLD mRNA upon compression, thereby stabilizing its mRNA and enhancing its expression.Fig. 5: HnRNPA0-dependent DLD mRNA stabilization supports tumor cell migration in confined spaces and promotes distant metastasis.Fig. 6: HnRNPA0-dependent DLD mRNA stabilization promotes tumor cell migration in confined spaces by malate–TUBA1B interaction.Fig. 7: A schematic model illustrating that compression-induced metabolic adaptation drives confined tumor cell migration and distant metastasis via malate-dependent microtubule reinforcement.

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Download referencesAcknowledgementsThis work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (CAS) (XDB0990000 to W.Y.); the National Natural Science Foundation of China (32025013, 32521007, 92357301 to W.Y.; 32200625 to M.L.; 82571814 to C.C.); the National Key R&D Program of China (2024YFA1306000 and 2022YFA0806200 to W.Y.); CAS Project for Young Scientists in Basic Research (YSBR-014); Science and Technology Commission of Shanghai Municipality (24J12800600); Shanghai Municipal Science and Technology Major Project, the Research Funds of Hangzhou Institute for Advanced Study UCAS (2025HIAS-ZL014). W.Y. is a SANS Exploration Scholar. This work is also supported by Shanghai Sailing Program (22YF1453900 to M.L.) and the Shanghai Postdoctoral Excellence Programme (2021379 to M.L.). We thank the Genome Tagging Project (GTP) Center and the Core Facilities of Center for Excellence in Molecular Cell Science (CEMCS) for technical support. We thank Mass Spectrometry System at the National Facility for Protein Science in Shanghai (NFPS). We thank Hong Li (Core Facility of Molecular Biology, CEMCS, CAS) and Xiaoyan Xu (Mass Spectrometry & Metabolomics Core Facility of Westlake University) for LC-MS/MS analysis. We gratefully acknowledge Prof. Xueliang Zhu (CEMCS, CAS, Shanghai, China) for generously providing the microtubule-related constructs. We thank Yazhuo Zhang (CEMCS, CAS, Shanghai, China) for her support with the animal experiments. We would like to thank Zhuo Yang and Hongwei Zhao (Chemical Biology Core Facility of CEMCS, CAS) for technical support. We thank Jinsong Li (CEMCS, CAS, Shanghai, China) for his assistance in analyzing the CRISPR-Cas9 screening data. We thank Huiying Chu (Liaoning Normal University) for elucidating the structural basis of the interaction between malate and microtubules. We thank Shanshan Qian (Mass Spectrometry System at the NFPS, Shanghai Advanced Research Institute, CAS, China) for data collection. We thank Jing Fan and Benhua Qiu (CEMCS, CAS, Shanghai, China) for their valuable suggestions of experiments. We also thank Cell Analysis Technology Platform, Animal Platform and Zebrafish Platform of CEMCS for technical support.Author informationAuthor notesThese authors contributed equally: Min Liu, Bing Liu, Chen Chen.Authors and AffiliationsKey Laboratory of Multi-cell Systems, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, ChinaMin Liu, Bing Liu, Xiaoyan Li, Dingpei Zhou, Hong Gao, Dong Gao, Yun Zhao & Weiwei YangDepartment of Radiation Oncology, Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, ChinaChen ChenShanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, ChinaYi-Ran Wang & Yan-Jun LiuDepartment of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, ChinaYajuan ZhangEndoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, ChinaXinyang Liu & Quanlin LiKey Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, ChinaYijun Qi & Weiwei YangNational Facility for Protein Science in Shanghai, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, ChinaChen SuShanghai Academy of Natural Sciences (SANS), Shanghai, ChinaWeiwei YangAuthorsMin LiuView author publicationsSearch author on:PubMed Google ScholarBing LiuView author publicationsSearch author on:PubMed Google ScholarChen ChenView author publicationsSearch author on:PubMed Google ScholarYi-Ran WangView author publicationsSearch author on:PubMed Google ScholarXiaoyan LiView author publicationsSearch author on:PubMed Google ScholarYajuan ZhangView author publicationsSearch author on:PubMed Google ScholarXinyang LiuView author publicationsSearch author on:PubMed Google ScholarDingpei ZhouView author publicationsSearch author on:PubMed Google ScholarHong GaoView author publicationsSearch author on:PubMed Google ScholarYijun QiView author publicationsSearch author on:PubMed Google ScholarChen SuView author publicationsSearch author on:PubMed Google ScholarDong GaoView author publicationsSearch author on:PubMed Google ScholarYun ZhaoView author publicationsSearch author on:PubMed Google ScholarYan-Jun LiuView author publicationsSearch author on:PubMed Google ScholarQuanlin LiView author publicationsSearch author on:PubMed Google ScholarWeiwei YangView author publicationsSearch author on:PubMed Google ScholarContributionsW.Y. conceived the study. W.Y. and M.L. designed the study. M.L. performed and analyzed the majority of the experiments and also contributed to data analyses and figure editing. B.L. contributed to the experimental work by assisting in animal experiments, CRISPR/Cas9 screening, plasmid construction, and data analyses. C.C. provided pathology and PDX assistance. Y.R.W. and Xiaoyan L. provided PDMS microchannel assistance. Yajuan Z. edited the manuscript and provided advice. Xinyang L. provided pathology assistance. D.Z. analyzed the CRISPR/Cas9 screening results. H.G. participated in reviewing and editing the manuscript. Y.Q. assisted in data analyses. C.S. performed the LiP-SMap analysis. D.G. and Yun Z. participated in reviewing the manuscript. Y.J.L. provided PDMS microchannel assistance and offered technical advice. Q.L. contributed reagents and pathological expertise, provided conceptual advice, and assisted in editing the manuscript. W.Y. wrote the manuscript with comments from all authors.Corresponding authorsCorrespondence to
Yan-Jun Liu, Quanlin Li or Weiwei Yang.Ethics declarations

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Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationVideo S13-shTUBA1B+WT (download AVI )Video S14-shTUBA1B+Mutant2 (download AVI )Video S1. 4 um-shNT (download MP4 )Video S2. 4 um-shDLD (download MP4 )Video S3. 4 um-shDLD+rDLD (download MP4 )Video S4. 6 um-shNT (download MP4 )Video S5. 6 um-shDLD (download MP4 )Video S6. 6um-shDLD+rDLD (download MP4 )Video S7. 8 um-shNT (download MP4 )Video S8. 8 um-shDLD (download MP4 )Video S9. 8 um-shDLD+rDLD (download MP4 )Video S10-ShNT (download MP4 )Video S11-shDLD-1 (download MP4 )Video S12-shDLD-2 (download MP4 )Supplementary Information, Figs. S1–S9 (download PDF )Supplementary Table 1 (download XLSX )Supplementary Table 2 (download XLSX )Supplementary Table 3 (download XLSX )Supplementary Table 4 (download XLSX )Supplementary Table 5 (download XLSX )Rights and permissionsSpringer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.Reprints and permissionsAbout this articleCite this articleLiu, M., Liu, B., Chen, C. et al. Compression-induced metabolic adaptation drives confined tumor cell migration and distant metastasis via malate-dependent microtubule reinforcement.
Cell Res 36, 513–530 (2026). https://doi.org/10.1038/s41422-026-01254-4Download citationReceived: 06 August 2025Accepted: 09 April 2026Published: 18 May 2026Version of record: 18 May 2026Issue date: July 2026DOI: https://doi.org/10.1038/s41422-026-01254-4