title: 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 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.
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center (UMC) Utrecht, 3584 CT Utrecht, The Netherlands.|Cancer Genomics Netherlands, UMC Utrecht, 3584 CG, Utrecht, The Netherlands.
authors.forename: Arianna
authors.initials: A
authors.lastname: Fumagalli
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center (UMC) Utrecht, 3584 CT Utrecht, The Netherlands.|Cancer Genomics Netherlands, UMC Utrecht, 3584 CG, Utrecht, The Netherlands.
authors.forename: Jarno
authors.initials: J
authors.lastname: Drost
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center (UMC) Utrecht, 3584 CT Utrecht, The Netherlands.|Cancer Genomics Netherlands, UMC Utrecht, 3584 CG, Utrecht, The Netherlands.
authors.forename: Saskia J E
authors.initials: SJ
authors.lastname: Suijkerbuijk
authors.affiliation: Cancer Genomics Netherlands, UMC Utrecht, 3584 CG, Utrecht, The Netherlands.|Department of Medical Genetics, UMC Utrecht, 3584 CX, Utrecht, The Netherlands.
authors.forename: Ruben
authors.initials: R
authors.lastname: van Boxtel
authors.affiliation: Cancer Genomics Netherlands, UMC Utrecht, 3584 CG, Utrecht, The Netherlands.|Department of Medical Genetics, UMC Utrecht, 3584 CX, Utrecht, The Netherlands.
authors.forename: Joep
authors.initials: J
authors.lastname: de Ligt
authors.affiliation: Department of Pathology, UMC Utrecht, 3584 CX, Utrecht, The Netherlands.
authors.forename: G Johan
authors.initials: GJ
authors.lastname: Offerhaus
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center (UMC) Utrecht, 3584 CT Utrecht, The Netherlands.|Cancer Genomics Netherlands, UMC Utrecht, 3584 CG, Utrecht, The Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: Begthel
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center (UMC) Utrecht, 3584 CT Utrecht, The Netherlands.|Cancer Genomics Netherlands, UMC Utrecht, 3584 CG, Utrecht, The Netherlands.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Beerling
authors.affiliation: Cancer Research UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, United Kingdom.
authors.forename: Ee Hong
authors.initials: EH
authors.lastname: Tan
authors.affiliation: Cancer Research UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, United Kingdom.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Cancer Genomics Netherlands, UMC Utrecht, 3584 CG, Utrecht, The Netherlands.|Department of Medical Genetics, UMC Utrecht, 3584 CX, Utrecht, The Netherlands.
authors.forename: Edwin
authors.identifier: 0000-0002-0400-9542
authors.initials: E
authors.lastname: Cuppen
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center (UMC) Utrecht, 3584 CT Utrecht, The Netherlands; h.clevers@hubrecht.eu j.vanrheenen@hubrecht.eu.|Cancer Genomics Netherlands, UMC Utrecht, 3584 CG, Utrecht, The Netherlands.|Princess Máxima Center for Pediatric Oncology, 3584 CT, Utrecht, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center (UMC) Utrecht, 3584 CT Utrecht, The Netherlands; h.clevers@hubrecht.eu j.vanrheenen@hubrecht.eu.|Cancer Genomics Netherlands, UMC Utrecht, 3584 CG, Utrecht, The Netherlands.
authors.forename: Jacco
authors.initials: J
authors.lastname: van Rheenen
mesh_terms: D000328:Adult; D000818:Animals; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005818:Genetic Engineering; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics; D009385:Neoplastic Processes; D009940:Organoids / Q000378:metabolism / Q000637:transplantation*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: adenoma-carcinoma sequence; colorectal cancer; metastasis; niche independence; organoids