Human adenoma-originating organoids as a model for colorectal cancer development

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome that predisposes to colorectal cancer (CRC). FAP patients typically develop hundreds to thousands of adenomas in the colon and rectum, which progress to cancer if not removed.

Adenomatous polyposis coli (APC) is tumor suppressor protein that is mutated in the vast majority of both sporadic and hereditary colorectal tumors. Around 30% of these mutations are nonsense mutations.

We have previously shown that aminoglycosides and macrolides antibiotics can induce nonsense mutation read-through and restore the expression and function of full-length APC protein in CRC cells and in mice expressing a mutant form of the APC protein. Furthermore, in a recent clinical trial, we have shown that treating FAP patients with macrolides leads to a decrease in cumulative adenoma burden.

Here we report the generation of functional adenoma-originating colonic organoids (colonoids) derived from patients harboring APC mutations. Aminoglycoside treatment of colonoids with APC- nonsense mutations induced a partial restoration of APC. We aim to further characterize and develop this model for studying the molecular implications of APC restoration. Furthermore, these organoids can provide a bona fide model for screening new read-through inducing agents and will assist in identifying specific tailored treatments against CRC and other nonsense mutation originating diseases.