2026-05-25 中国科学院（CAS）
＜関連情報＞
- https://english.cas.cn/newsroom/research-news/202605/t20260522_1159785.shtml
- https://www.nature.com/articles/s41422-026-01254-4
圧縮によって誘発される代謝適応は、リンゴ酸依存性微小管強化を介して、腫瘍細胞の限定された移動と遠隔転移を促進する Compression-induced metabolic adaptation drives confined tumor cell migration and distant metastasis via malate-dependent microtubule reinforcement
Min Liu,Bing Liu,Chen Chen,Yi-Ran Wang,Xiaoyan Li,Yajuan Zhang,Xinyang Liu,Dingpei Zhou,Hong Gao,Yijun Qi,Chen Su,Dong Gao,Yun Zhao,Yan-Jun Liu,Quanlin Li & Weiwei Yang
Cell Research Published:18 May 2026
DOI:https://doi.org/10.1038/s41422-026-01254-4
Abstract
Metastasis, 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.
