Metastasis accounts for over 90% of cancer-related deaths and remains the most lethal phase of cancer progression. During metastasis, cancer cells must navigate through physically confined microenvironments such as dense extracellular matrices, narrow capillaries, and endothelial gaps. It is well-established that cancer cells reprogram their metabolism to facilitate progression, but the specific metabolic adaptations that enable them to overcome these physical barriers and drive distant metastasis remain elusive.

In a study published in Cell Research, a team led by Prof. YANG Weiwei from the Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences, along with Prof. LI Quanlin from Zhongshan Hospital, Fudan University, and Prof. LIU Yanjun from Fudan University, elucidated the molecular mechanism by which Dihydrolipoamide Dehydrogenase (DLD) responds to mechanical pressure signals to enhance tumor cell migration in confined spaces, thereby promoting tumor metastasis.

Through a CRISPR screen targeting 1,685 metabolic enzymes, the researchers identified the mitochondrial enzyme DLD as a critical factor for tumor cell migration in confined environments.

Mechanistically, when tumor cells encounter physical compression, the intracellular heterogeneous nuclear ribonucleoprotein A0 (hnRNPA0) binds to the 3' untranslated region of DLD mRNA, enhancing its stability and leading to a specific upregulation of DLD protein during confined migration. The elevated DLD enhances the metabolic activity of the mitochondrial tricarboxylic acid cycle, resulting in an accumulation of the intermediate metabolite malate. In this context, malate functions not merely as a metabolic intermediate but also as a key signaling molecule that binds to tubulin alpha-1B chain (TUBA1B), promoting microtubule assembly.

Using gene knock-in techniques, the researchers generated DLD mutants lacking the hnRNPA0 binding site or directly disrupted the malate-TUBA1B interaction. Both interventions significantly inhibited confined migration and distant metastasis, validating the core role of this pathway. Furthermore, analysis of colorectal cancer patient samples revealed that DLD is upregulated in cancer cells within tumor capillaries and is correlated with metastatic recurrence, highlighting its clinical significance.

This study delineates a complete signaling axis connecting "mechanical pressure" to "metabolic reprogramming" and "cytoskeletal remodeling." It provides insights into the molecular mechanisms of metastasis and lays a foundation for clinical intervention. The identified hnRNPA0-DLD-malate axis and the strategy of disrupting the malate-TUBA1B interaction offer precise therapeutic targets for the development of novel anti-metastatic drugs targeting metabolism-cytoskeleton interactions.