Abstract
The phenotypic spectrum of colorectal cancer (CRC) is remarkably diverse, with seemingly endless variations in cell shape, mitotic figures and multicellular configurations. Despite this morphological complexity, histological grading of collective phenotype patterns provides robust prognostic stratification in CRC. Although mechanistic understanding is incomplete, previous studies have shown that the cortical protein ezrin controls diversification of cell shape, mitotic figure geometry and multicellular architecture, in 3D organotypic CRC cultures. Because ezrin is a substrate of Src tyrosine kinase that is frequently overexpressed in CRC, we investigated Src regulation of ezrin and morphogenic growth in 3D CRC cultures. Here we show that Src perturbations disrupt CRC epithelial spatial organisation. Aberrant Src activity suppresses formation of the cortical ezrin cap that anchors interphase centrosomes. In CRC cells with a normal centrosome number, these events lead to mitotic spindle misorientation, perturbation of cell cleavage, abnormal epithelial stratification, apical membrane misalignment, multilumen formation and evolution of cribriform multicellular morphology, a feature of low-grade cancer. In isogenic CRC cells with centrosome amplification, aberrant Src signalling promotes multipolar mitotic spindle formation, pleomorphism and morphological features of high-grade cancer. Translational studies in archival human CRC revealed associations between Src intensity, multipolar mitotic spindle frequency and high-grade cancer morphology. Collectively, our study reveals Src regulation of CRC morphogenic growth via ezrin-centrosome engagement and uncovers combined perturbations underlying transition to high-grade CRC morphology. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Highlights
For over a century, histological grading of cellular and multicellular morphology has provided a robust readout of cancer aggressiveness [1]
We show that Src perturbation of ezrin cap formation in cells with a normal centrosome number leads to misorientation of the mitotic spindle
Src regulates ezrin via molecular crosstalk To dissect molecular crosstalk underlying colorectal cancer (CRC) morphology, we explored Src interactions with phosphatase and tensin homologue (PTEN), using isogenic stable PTEN-expressing or -deficient Caco-2 and HCT116 CRC cells
Summary
Histological grading of cellular and multicellular morphology has provided a robust readout of cancer aggressiveness [1]. The cortex comprises the cell membrane linked to the underlying actin cytoskeleton meshwork by ezrin, radixin or moesin (ERM) proteins [5]. Ezrin and other ERM molecules are redistributed within the cortex to sustain mechanical stability [7,8] and to form a polarised accumulation called the ezrin cap, which provides a cue for centrosome anchoring [9]. These processes set bipolar symmetry for mitotic fidelity and control of emergent tissue properties [9,10]
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