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

Abstract

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.

Keywords:

• Colorectal cancer
• organoids
• single cell RNAseq
• consensus molecular subtypes

Acknowledgments

This review was prompted by a recent (2022) annual scientific meeting of the Australasian Gastrointestinal Trials Group (AGITG). Presentations by Professors Robert Coffee and Iain Tan sowed the seeds that guided the emphasis and selective nature of the work reported herein. Interest in the use of organoids as tools for research discovery and patient care has been a long-standing effort of the Australian Living Organoids Alliance (ALOA) championed by Prof Antony Burgess and supported by the time when Prof Hans Clevers served a sabbatical at the Walter and Elisa Hall Institute in Melbourne, Australia. We wish to thank the many Ramsay lab members and collaborators (clinicians and scientists) who have toiled in the operating theatre and tissue culture biohazard cabinets learning the mysteries of organoid and tumoroid propagation. Thank you to the ongoing funding of the National Health and Medical Research Council for support and finally the many patients who have consented to participate in our research; this work is ultimately for you.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

RGR and VW receive research support from the National Health and Medical Research Council.