Tumor metastasis is the leading cause of cancer-related deaths, driven by the long-distance migration of tumor cells through complex in vivo microenvironments. Specifically, when tumor cells traverse narrow and confining spaces (such as the pores of the extracellular matrix, fibrotic tissue spaces, or tiny capillaries), their ability to migrate under confinement directly determines the success of the metastatic process. Therefore, a deep understanding of tumor cell migration under confining conditions is crucial for revealing the essence of metastasis and developing intervention strategies.
In a study published in Nature Communications, a research team led by Prof. Weiwei Yang from the Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences, collaborated with Prof. Feng Yao at Shanghai Chest Hospital and the team led by Bangbao Tao at Xinhua Hospital, Shanghai Jiao Tong University. The study, titled “Compression-induced NF-κB activation sustains tumor cell survival in confinement by detoxifying aldehydes and promotes metastasis”, revealed the specific molecular mechanism by which mechanical compression in confining environments sustains tumor cell survival and promotes distant metastasis through aldehyde dehydrogenase ALDH1B1-mediated remodeling of aldehyde metabolism.
Notably, metabolic remodeling is a well-established hallmark of tumor development, and each stage of metastasis is accompanied by specific metabolic adaptations. However, it remains unclear how tumor cells, under sustained mechanical compression in such confining physical microenvironments, dynamically reprogram their metabolism to maintain energy supply, ensure structural integrity, and ultimately achieve survival and migration. Elucidating this "mechano-metabolic" coupling mechanism would provide a new perspective for understanding the underlying drivers of tumor metastasis.
This study employed a CRISPR/Cas9 in vivo screening system targeting 1,685 metabolic enzymes and identified that aldehyde dehydrogenase ALDH1B1 is a key factor for tumor cell survival in pulmonary capillaries.
Mechanistic analysis revealed that mechanical compression enhances the interaction between CSK23 and IKKβ kinase, leading to phosphorylation of IKKβ at serine residues 177 and 181, which activates the NF-κB signaling pathway and ultimately upregulates ALDH1B1 expression. Upregulation of ALDH1B1 enhance tumor cells’ aldehyde detoxification capacity, inhibits ferroptosis, promotes tumor cell survival in confining vascular environment, thereby driving lung cancer metastasis.
In summary, this work unveils a new mechanism whereby mechanical force remodels aldehyde metabolism to regulate cell death and highlights its critical role in tumor metastasis. This discovery not only deepens our understanding of tumor cell survival in confining microenvironments but also provides a new direction for developing anti-metastasis strategies targeting CSK23 or ALDH1B1.
Reference: https://www.nature.com/articles/s41467-025-67452-7
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