Untangling the complexities of micropapillary cancer

Distinct morphological subtypes of colorectal cancer (CRC) confer a bleak clinical outlook. In a recent issue of The Journal of Pathology, Onuma et al investigated morphological evolution of a highly fatal CRC subtype known as micropapillary cancer (MPC). This study enhances understanding of MPC biology including essential regulatory signals, cellular and multicellular phenotypes, as well as cancer behaviour. Iterative modelling in three-dimensional (3D) patient-derived CRC tissue-originated spheroids (CTOSs) revealed spatiotemporal oscillations of Rho-ROCK hyperactivity underlying reversal of membrane polarity and suppression of lumen formation during development of multicellular MPC morphology. Corroborative studies in CTOSs, xenografts, and archival human CRCs confirm human disease relevance. Although cancer morphology has previously been considered irreversible, targeted inhibition of Rho-ROCK activity restored membrane polarity, lumenized multicellular assembly, and suppressed MPC morphology in 3D CTOS cultures and xenografts. Collectively, the study identifies molecular, biophysical, and multicellular mechanisms implicated in morphological evolution of micropapillary CRC. (C) 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Automated summary

The study investigated the morphological evolution of a highly fatal subtype of colorectal cancer known as micropapillary cancer (MPC). Through iterative modeling in 3D patient-derived CRC tissue-originated spheroids (CTOSs), the study revealed spatiotemporal oscillations of Rho-ROCK hyperactivity underlying membrane polarity reversal and lumen formation suppression. Targeted inhibition of Rho-ROCK activity restored membrane polarity and lumenized multicellular assembly in 3D CTOS cultures and xenografts.