Technological advances define shifting pathway signaling from normal to primary and metastatic colorectal cancer

Adoption of organoid/tumoroid propagation of normal and malignant intestinal epithelia has provided unparalleled opportunities to compare cell growth factor and signaling dependencies. These 3D structures recapitulate tumours in terms of gene expression regarding the tumor cells but also allow deeper insights into the contribution of the tumour microenvironment (TME). Elements of the TME can be manipulated or added back in the form of infiltrating cytotoxic lymphocytes and/or cancer associated fibroblasts. The effectiveness of chemo-, radio- and immunotherapies can be explored within weeks of deriving these patient-derived tumour avatars informing treatment of these exact patients in a timely manner. Entrenched paths to colorectal cancer (CRC) from the earliest steps of conventional adenoma or serrated lesion formation, and the recognition of further sub-categorisations embodied by consensus-molecular-subtypes (CMS), provide genetic maps allowing a molecular form of pathologic taxonomy. Recent advances in organoid propagation and scRNAseq are reshaping our understanding of CMS and CRC.