Colorectal cancer (CRC) diagnosis and prognostic stratification are based on histopathologic assessment of cell or nuclear pleomorphism, aberrant mitotic figures, altered glandular architecture, and other phenomic abnormalities. This complexity is driven by oncogenic perturbation of tightly coordinated spatiotemporal signaling to disrupt multiple scales of tissue organization. This review clarifies molecular and cellular mechanisms underlying common CRC histologic features and helps understand how the CRC genome controls core aspects of tumor aggressiveness. It further explores a spatiotemporal framework for CRC phenomics based on regulation of living cells in fundamental and organotypic model systems. The review also discusses tissue homeostasis, considers distinct classes of oncogenic perturbations, and evolution of cellular or multicellular cancer phenotypes. It further explores the molecular controls of cribriform, micropapillary, and high-grade CRC morphology in organotypic culture models and assesses relevant translational studies. In addition, the review delves into complexities of morphologic plasticity whereby a single molecular signature generates heterogeneous cancer phenotypes, and, conversely, morphologically homogeneous tumors show substantive molecular diversity. Principles outlined may aid mechanistic interpretation of omics data in a setting of cancer pathology, provide insight into CRC consensus molecular subtypes, and better define principles for CRC prognostic stratification.

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.

This study aimed to assess whether a daily supplementation with Lactobacillus rhamnosus GG (LGG) can alter the body composition as well as bone turnover and the mechanical properties of the bones in systemic immunodeficiency. For this, we use an in vivo model of severe combined immunodeficient (scid) mice supplemented daily with LGG over 8 weeks period. After 8 weeks of the treatment, the animals were assessed by DEXA and then the blood was collected from the hepatic portal vein for bone turnover biomarkers; post-mortem, the caecum was removed for isolation and enumeration of the gut bacteria, while femurs/tibiae were excised for the assessment of their mechanical properties. LGG treatment affected the composition of the gut microbiota at the order level, and it decreased (P = 0.002) total adipose tissue content. Moreover, LGG treatment decreased the stiffness (N/mm) of both femurs (P = 0.008) and tibiae (P = 0.011). To conclude, this study shows that dietary supplementation with LGG in immunodeficient animals can alter mechanical properties of the long bones and concomitantly it can modify host's total adiposity level.

No abstract