Fundamental control of grade‐specific colorectal cancer morphology by Src regulation of ezrin–centrosome engagement

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.

Tissue architecture in tumor initiation and progression

“…Using tissue clearing of prostate resections, a staging method based on 3D architecture of prostate lesions has demonstrated prognostic value [4]. In CRC, tissue architecture informs on Src activity because Src induces ezrin which changes the morphology of cells and multicellular structures, informing on prognosis [86].…”

Ezrin expression in female reproductive tissues: A review of regulation and pathophysiological implications

“…Initial studies demonstrated that the critical T567 on C-ERMAD could be phosphorylated by Rho-kinase (ROCK) ( Ding et al, 2022 ), STE20-like protein kinase (SLK) ( Garland et al, 2021 ), lymphocyte-oriented kinase (LOK) ( Senju and Tsai, 2022 ) and protein kinase C(PKC) ( Khan et al, 2022 ) both in the laboratory and in living organisms. Ezrin Y145, Y353 and Y477 can be modified by phosphorylation through the action of Src kinases and the intrinsic Tyr kinase activity of receptors for epidermal growth factor, hepatocyte growth factor and Platelet-derived growth factor ( Huang et al, 2018 ; Derouiche and Geiger, 2019 ; Rainey et al, 2020 ).…”