te Boekhorst, Veronika and Jiang, Liying and Mählen, Marius and Meerlo, Maaike and Dunkel, Gina and Durst, Franziska C. and Yang, Yanjun and Levine, Herbert and Burgering, Boudewijn M. T. and Friedl, Peter (2022) Calpain-2 regulates hypoxia/HIF-induced plasticity toward amoeboid cancer cell migration and metastasis. CURRENT BIOLOGY, 32 (2). 412-427.e8. ISSN 0960-9822, 1879-0445
Full text not available from this repository. (Request a copy)Abstract
Hypoxia, through hypoxia inducible factor (HIF), drives cancer cell invasion and metastatic progression in various cancer types. In epithelial cancer, hypoxia induces the transition to amoeboid cancer cell dissemination, yet the molecular mechanisms, relevance for metastasis, and effective intervention to combat hypoxia-induced amoeboid reprogramming remain unclear. Here, we identify calpain-2 as a key regulator and anti-metastasis target of hypoxia-induced transition from collective to amoeboid dissemination of breast and head and neck (HN) carcinoma cells. Hypoxia-induced amoeboid dissemination occurred through low extracellular matrix (ECM)-adhesive, predominantly bleb-based amoeboid movement, which was maintained by a low-oxidative and -glycolytic energy metabolism ("eco-mode"). Hypoxia induced calpain-2-mediated amoeboid conversion by deactivating beta 1 integrins through enzymatic cleavage of the focal adhesion adaptor protein talin-1 Consequently, targeted downregulation or pharmacological inhibition of calpain-2 restored talin-1 integrity and beta 1 integrin engagement and reverted amoeboid to elongated phenotypes under hypoxia. Calpain-2 activity was required for hypoxia-induced amoeboid conversion in the orthotopic mouse dermis and upregulated in invasive HN tumor xenografts in vivo, and attenuation of calpain activity prevented hypoxia-induced metastasis to the lungs. This identifies the calpain-2/talin-1/beta 1 integrin axis as a druggable mechanosignaling program that conserves energy yet enables metastatic dissemination that can be reverted by interfering with calpain activity.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TUMOR HYPOXIA; IN-VIVO; ADHESION; INVASION; GROWTH; HIF-1-ALPHA; TRANSITION; INHIBITION; EXPRESSION; TALIN |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Zentren des Universitätsklinikums Regensburg > Regensburger Centrum für Interventionelle Immunologie (RCI) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 30 Jan 2024 05:42 |
| Last Modified: | 30 Jan 2024 05:42 |
| URI: | https://pred.uni-regensburg.de/id/eprint/58451 |
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