TY - JOUR
T1 - Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids
AU - Fumagalli, A.
AU - Drost, J.
AU - Suijkerbuijk, S.J.E.
AU - Van Boxtel, R.
AU - De Ligt, J.
AU - Offerhaus, G.J.
AU - Begthel, H.
AU - Beerling, E.
AU - Tan, E.H.
AU - Sansom, O.J.
AU - Cuppen, E.
AU - Clevers, H.
AU - Van Rheenen, J.
PY - 2017
Y1 - 2017
N2 - 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 accumulation of oncogenic mutations in Wnt, EGFR, P53, and TGF-β signaling pathways 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.
AB - 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 accumulation of oncogenic mutations in Wnt, EGFR, P53, and TGF-β signaling pathways 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.
UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-85016113409&partnerID=MN8TOARS
U2 - 10.1073/pnas.1701219114
DO - 10.1073/pnas.1701219114
M3 - Article
SN - 0027-8424
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
ER -