Shortcuts to Intestinal Carcinogenesis by Genetic Engineering in Organoids

Abstract

Inactivation of the Adenomatous Polyposis Coli (APC) gene is an initiating and the most relevant event in the majority of sporadic cases with colorectal cancer, providing a rationale for using Apc‐mutant mice as the disease model. Whereas carcinogenesis has been observed only at the organism level, the recent development of organoid culture technique has enabled long‐term propagation of intestinal stem cells in a physiological setting, raising the possibility that organoids could serve as an alternative platform for modeling colon carcinogenesis. Indeed, we demonstrated that lentivirus‐based RNAi‐mediated knockdown of Apc in intestinal organoids gave rise to subcutaneous tumors upon inoculation in immmunodeficient mice. Reconstitution of common genetic aberrations in organoids resulted in development of various lesions ranging from aberrant crypt foci to full‐blown cancer, recapitulating multi‐step colorectal tumorigenesis. Due to its simplicity and utility, similar organoid‐based approaches have been applied to both murine and human cells in many investigations, to gain mechanistic insights into tumorigenesis, validate putative tumor suppressor genes or oncogenes, and establish preclinical models for drug discovery. In this review article, we provide a multifaceted overview of these types of approaches that will likely accelerate and advance research on colon cancer.

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