The van Rheenen group together with the Clevers group have their PNAS paper out today, titled: Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids.

Abstract: In the adenoma-carcinoma sequence, it is proposed that intestinal polyps evolve through a set of defined mutations toward metastatic colorectal cancer (CRC). Here, we dissect this adenoma-carcinoma sequence in vivo by using an orthotopic organoid transplantation model of human colon organoids engineered to harbor different CRC mutation combinations. We demonstrate that sequential accu- mulation of oncogenic mutations in Wnt, EGFR, P53, and TGFβ sig- naling pathways (APC, p53, KRAS and SMAD mutations) facilitates efficient tumor growth, migration, and metastatic colonization. We show that reconstitution of specific niche signals can restore metastatic growth potential of tumor cells lacking one of the oncogenic mutations. Our findings imply that the ability to metastasize—i.e., to colonize distant sites—is the direct consequence of the loss of dependency on specific niche signals.

In the figure below it is clearly visible that only the quadruple – the transplanted tissue with all four mutations – lead to matastasis of the cancer cells, spreading out to liver and/or lung. The tissue with no SMAD4 defect but only APC, P53 and KRAS also showed some activity which could be enhanced with extra growth factors. The latter indicates that the cancer cells are able to grow in ‘alien’ environments like the liver, that lack specific niche signals (growth factors).

Read the whole paper online at PNAS: Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids.