Phosphoinositide species and filamentous actin formation mediate engulfment by senescent tumor cells

• Published in: PLoS biology Vol. 20; no. 10; p. e3001858
• Main Authors: Frey, Wesley D, Anderson, Ashlyn Y, Lee, Hyemin, Nguyen, Julie B, Cowles, Emma L, Lu, Hua, Jackson, James G
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 24.10.2022; Public Library of Science (PLoS)
• Subjects: Actin; Actin Cytoskeleton - metabolism; Actins - metabolism; Animals; Biology and Life Sciences; Biosensors; Breast cancer; Cannibalism; Cell cycle; Chemotherapy; Clathrin; Cytoplasm; Ecology and Environmental Sciences; Engineering and Technology; Genotype & phenotype; Humans; Internalization; Kinases; Localization; Macrophages; Medicine and Health Sciences; Mice; Microscopy; Phagocytosis; Phagocytosis - physiology; Phenotypes; Phosphatidylinositol Phosphates - metabolism; Predators; Prey; Research and Analysis Methods; Senescence; Tumor cells; Tumors
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3001858

Cancer cells survive chemotherapy and cause lethal relapse by entering a senescent state that facilitates expression of many phagocytosis/macrophage-related genes that engender a novel cannibalism phenotype. We used biosensors and live-cell imaging to reveal the basic steps and mechanisms of engulfment by senescent human and mouse tumor cells. We show filamentous actin in predator cells was localized to the prey cell throughout the process of engulfment. Biosensors to various phosphoinositide (PI) species revealed increased concentration and distinct localization of predator PI(4) P and PI(4,5)P2 at the prey cell during early stages of engulfment, followed by a transient burst of PI(3) P before and following internalization. PIK3C2B, the kinase responsible for generating PI(3)P, was required for complete engulfment. Inhibition or knockdown of Clathrin, known to associate with PIK3C2B and PI(4,5)P2, severely impaired engulfment. In sum, our data reveal the most fundamental cellular processes of senescent cell engulfment, including the precise localizations and dynamics of actin and PI species throughout the entire process.