Compression-induced NF-κB activation sustains tumor cell survival in confinement by detoxifying aldehydes and promotes metastasis

TL;DR

Cancer cells survive in tight spaces by using a pathway that detoxifies harmful chemicals, helping them spread to other parts of the body.

Contribution

A mechano-metabolic pathway involving CSK23, NF-κB, and ALDH1B1 is identified as critical for tumor cell survival in confined environments.

Findings

ALDH1B1 is essential for tumor cell survival in confining capillaries.

CSK23 phosphorylates IKKβ to activate NF-κB, which upregulates ALDH1B1.

Inhibiting CSK23 or ALDH1B1 reduces metastasis in lung cancer patients.

Abstract

Metastasis remains the primary cause of cancer-related mortality. During dissemination, cancer cells must navigate spatially confined microenvironments, yet the underlying metabolic adaptations that facilitate this process remain unclear. Here, through an in vivo CRISPR screen targeting metabolic enzymes, we identify aldehyde dehydrogenase 1 family member B1 (ALDH1B1) as essential for tumor cell survival in confining capillaries. Mechanistically, compressive force induces casein kinase 2 alpha 3 (CSK23) to phosphorylate kappa-B kinase subunit beta (IKKβ) at Ser177/181, which activates the nuclear factor kappa B (NF-κB) pathway and upregulates ALDH1B1. The upregulation of ALDH1B1 enhances aldehyde detoxification, which suppresses ferroptosis and promotes tumor cell survival during migration through the capillaries, thereby facilitating metastasis. Importantly, genetic or pharmacological inhibition of CSK23 or ALDH1B1 effectively impairs metastasis. In lung cancer patients, confined tumor cells exhibit higher levels of ALDH1B1 and NF-κB activation, which correlates with metastatic recurrence. Our findings reveal a mechano-metabolic pathway that promotes metastasis and suggest CSK23 and ALDH1B1 as potential therapeutic targets.

To establish metastasis, cancer cells need to adapt in order to navigate through confined spaces. Here, the authors discover that compression force-induced CSK23-mediated NF-κB activation regulates ALDH1B1 expression, ultimately modulating ferroptosis and tumor cell survival in confining capillaries.

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