Abstract
Histological grading provides prognostic stratification of colorectal cancer (CRC) by scoring heterogeneous phenotypes. Features of aggressiveness include aberrant mitotic spindle configurations, chromosomal breakage, and bizarre multicellular morphology, but pathobiology is poorly understood. Protein kinase C zeta (PKCz) controls mitotic spindle dynamics, chromosome segregation, and multicellular patterns, but its role in CRC phenotype evolution remains unclear. Here, we show that PKCz couples genome segregation to multicellular morphology through control of interphase centrosome anchoring. PKCz regulates interdependent processes that control centrosome positioning. Among these, interaction between the cytoskeletal linker protein ezrin and its binding partner NHERF1 promotes the formation of a localized cue for anchoring interphase centrosomes to the cell cortex. Perturbation of these phenomena induced different outcomes in cells with single or extra centrosomes. Defective anchoring of a single centrosome promoted bipolar spindle misorientation, multi‐lumen formation, and aberrant epithelial stratification. Collectively, these disturbances induce cribriform multicellular morphology that is typical of some categories of low‐grade CRC. By contrast, defective anchoring of extra centrosomes promoted multipolar spindle formation, chromosomal instability (CIN), disruption of glandular morphology, and cell outgrowth across the extracellular matrix interface characteristic of aggressive, high‐grade CRC. Because PKCz enhances apical NHERF1 intensity in 3D epithelial cultures, we used an immunohistochemical (IHC) assay of apical NHERF1 intensity as an indirect readout of PKCz activity in translational studies. We show that apical NHERF1 IHC intensity is inversely associated with multipolar spindle frequency and high‐grade morphology in formalin‐fixed human CRC samples. To conclude, defective PKCz control of interphase centrosome anchoring may underlie distinct categories of mitotic slippage that shape the development of low‐ or high‐grade CRC phenotypes. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Highlights
Colorectal cancer (CRC) may represent the major cancer challenge of the 21st century because it is the third most lethal global malignancy and its incidence is expected to increase by 60% over the two decades [1]
PKCzI treatment reduced the percentage of Caco-2 cells showing cortical localization of merlin from 32.7 ± 2.90% in control cells to 13.3 ± 2.0% after PKCzI treatment (p = 0.02)
We show that Protein kinase C zeta (PKCz) couples genome segregation to multicellular assembly by control of interphase centrosome anchoring
Summary
Colorectal cancer (CRC) may represent the major cancer challenge of the 21st century because it is the third most lethal global malignancy and its incidence is expected to increase by 60% over the two decades [1]. Centrosome anchoring to the cell cortex is necessary for separation of mother and daughter centrosomes [11], construction and orientation of the mitotic spindle [12], formation of cell shape [13], and multicellular assembly [12]. Effective clustering of extra centrosomes during interphase enables assembly of a bipolar mitotic spindle, error-free segregation of a diploid chromosome complement [16], and normal multicellular pattern formation [10]. Ineffective clustering of interphase centrosomes can activate failsafe processes that cluster extra centrosomes later in the cell cycle, during metaphase [16]. These metaphase centrosome clustering processes invoke substantive segregation error [16]
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