title: Competition between human cells by entosis.
abstract: Human carcinomas are comprised of complex mixtures of tumor cells that are known to compete indirectly for nutrients and growth factors. Whether tumor cells could also compete directly, for example by elimination of rivals, is not known. Here we show that human cells can directly compete by a mechanism of engulfment called entosis. By entosis, cells are engulfed, or cannibalized while alive, and subsequently undergo cell death. We find that the identity of engulfing ("winner") and engulfed ("loser") cells is dictated by mechanical deformability controlled by RhoA and actomyosin, where tumor cells with high deformability preferentially engulf and outcompete neighboring cells with low deformability in heterogeneous populations. We further find that activated Kras and Rac signaling impart winner status to cells by downregulating contractile myosin, allowing for the internalization of neighboring cells that eventually undergo cell death. Finally, we compute the energy landscape of cell-in-cell formation, demonstrating that a mechanical differential between winner and loser cells is required for entosis to proceed. These data define a mechanism of competition in mammalian cells that occurs in human tumors.
authors.affiliation: 1] Laboratory of Cell Engineering, Institute of Biotechnology, Beijing 100071, China [2] Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Tianzhi
authors.initials: T
authors.lastname: Luo
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Signalling Programme, The Babraham Institute, Cambridge, CB22 3AT, UK.
authors.forename: Oliver
authors.initials: O
authors.lastname: Florey
authors.affiliation: Department of Cell Biology, School of Medicine, Fukuoka University, Fukuoka 814-0180, Japan.
authors.forename: Senji
authors.initials: S
authors.lastname: Shirasawa
authors.affiliation: Department of Pathology, Research Institute, International Medical Center of Japan, Tokyo 163-8655, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasazuki
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Douglas N
authors.initials: DN
authors.lastname: Robinson
authors.affiliation: 1] Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA [2] BCMB Allied Program, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Overholtzer
mesh_terms: D000205:Actomyosin / Q000378:metabolism; D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation; D057691:Entosis; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D016513:Mice, SCID; D009218:Myosins / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D034622:RNA Interference; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011725:Pyridines; C107953:RAC1 protein, human; C108830:Y 27632; D000205:Actomyosin; C515851:ROCK1 protein, human; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases; D009218:Myosins; D016283:Proto-Oncogene Proteins p21(ras); D020830:rac1 GTP-Binding Protein; D018631:ras Proteins; D020742:rhoA GTP-Binding Protein