Mechanisms by which centrosome aberrations promote tumor progression. (A) Centrosome amplification impairs normal asymmetric division, leading to expansion of stem cell population and tissue outgrowth. (Left) Asymmetric division of neuroblasts in Drosophila melanogaster determines the pools of differentiated neurons and dividing stem cells, maintaining tissue homeostasis. This process depends on asymmetric maturation of two centrosomes (2C) and their interaction with the cell cortex, segregating different cell fate determinants into each of two daughter cells. (Right) In cells with centrosome amplification (>2C, over 2 centrosomes), asymmetric cell division is disrupted by centrosome clustering, resulting in symmetric cell division. Subsequently, symmetric division leads to uncontrolled proliferation of self-renewing neural stem cells and tissue overgrowth. (B) Centrosome amplification induces chromosomal instability (CIN), leading to numerical and structural aberrations of chromosomes frequently found in cancers. Mitotic centrosome clustering leads to an elevated rate of chromosome segregation errors due to incorrect merotelic attachment (not shown), generating lagging chromosomes. Unequal segregation of lagging chromosomes generates aneuploidy, producing progenies with chromosome gain (e.g. oncogenes) or loss (e.g. tumor suppressor genes). In addition, lagging chromosome and subsequent formation of micronucleus can drive chromothripsis, localized and extensive chromosome rearrangements through chromosome shattering and rejoining. (C) Centrosome aberrations promote invasive properties. Mechanisms by which centrosome amplification (left) or structural defects (right) induce invasive behaviors are categorized, according to cell autonomous (top) or non-cell autonomous (down) mode of regulation. (1) Centrosome amplification induces cell autonomous invasion through increased microtubule (MT) nucleation followed by the activation of small GTPase Rac1. (2) Cells with extra centrosomes induce non-cell autonomous invasion through increased secretion that are mediated by extra centrosome-associated secretory phenotype (ECASP) or small extracellular vesicles (small EVs). Both secretions are mediated by increased reactive oxygen species (ROS) resulting from centrosome amplification. (3) NLP overexpression-mediated structural aberrations of centrosomes facilitate mitotic cell budding in non-cell autonomous manner. Within epithelia, cells expressing an elevated level of NLP is stiffer with weakened E-cadherin-mediated cell adherence junctions, squeezing out mitotic cells containing normal centrosomes to be disseminated. (4) Structural centrosome aberrations induced by overexpression of NLP or CEP131 lead to basal extrusion of damaged cells by mispositioning of contractile actomyosin ring.
