Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids

Arianna Fumagalli, Jarno Drost, Saskia J E Suijkerbuijk, Ruben van Boxtel, Joep de Ligt, G Johan Offerhaus, Harry Begthel, Evelyne Beerling, Ee Hong Tan, Owen J Sansom, Edwin Cuppen, Hans Clevers, Jacco van Rheenen

Research output: Contribution to journalArticlepeer-review

171 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)E2357-E2364
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number12
Publication statusPublished - 21 Mar 2017


  • Adult
  • Animals
  • Cell Movement
  • Colorectal Neoplasms/genetics
  • Disease Models, Animal
  • ErbB Receptors/genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genetic Engineering
  • Humans
  • Male
  • Mice
  • Mice, Inbred NOD
  • Middle Aged
  • Mutation
  • Neoplasm Metastasis/genetics
  • Neoplastic Processes
  • Organoids/metabolism
  • Signal Transduction
  • Transforming Growth Factor beta/metabolism


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