期刊
MOLECULAR BIOLOGY OF THE CELL
卷 32, 期 18, 页码 1772-1791出版社
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E21-04-0174
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资金
- National Heart, Lung and Blood Institute (NHLBI) Light Microscopy Core Facility
- intramural research programs of the NHLBI
- National Institute of Biomedical Imaging and Bioengineering
- Distinguished Scholars Program, Office of the Director at the National Institutes of Health
- Rubicon Grant from the Dutch Research Council (NWO) [82515005]
The study revealed the plasticity of migration modes in cancer cells migrating in confined microenvironments, particularly showing leader bleb-based migration in nonadhesive environments. Fluorescently tagged organelle-specific markers and actin-associated proteins localization demonstrated the crucial role of specific actin crosslinkers in LBBM.
Cancer cells migrating in confined microenvironments exhibit plasticity of migration modes. Confinement of contractile cells in a nonadhesive environment drives leader bleb-based migration (LBBM), morphologically characterized by a long bleb that points in the direction of movement separated from a cell body by a contractile neck. Although cells undergoing LBBM have been visualized within tumors, the organization of organelles and actin regulatory proteins mediating LBBM is unknown. We analyzed the localization of fluorescent organelle-specific markers and actin-associated proteins in human melanoma and osteosarcoma cells undergoing LBBM. We found that organelles from the endolysosomal, secretory, and metabolic systems as well as the vimentin and microtubule cytoskeletons localized primarily in the cell body, with some endoplasmic reticulum, microtubules, and mitochondria extending into the leader bleb. Overexpression of fluorescently tagged actin regulatory proteins showed that actin assembly factors localized toward the leader bleb tip, contractility regulators and cross-linkers in the cell body cortex and neck, and cross-linkers additionally throughout the leader bleb. Quantitative analysis showed that excess filamin-A and fascin-1 increased migration speed and persistence, while their depletion by small interfering RNA indicates a requirement in promoting cortical tension and pressure to drive LBBM. This indicates a critical role of specific actin crosslinkers in LBBM.
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