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; George Johan Offerhaus; Harry Begthel; Evelyne Beerling; Ee Hong Tan; Owen J Sansom; Edwin Cuppen; Hans Clevers; Jacco van Rheenen

doi:10.1073/pnas.1701219114

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, George Johan Offerhaus, Harry Begthel, Evelyne Beerling, Ee Hong Tan, Owen J Sansom, Edwin Cuppen, Hans Clevers, Jacco van Rheenen

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

192 Citations (Scopus)

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.

Original language	English
Pages (from-to)	E2357-E2364
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	114
Issue number	12
DOIs	https://doi.org/10.1073/pnas.1701219114
Publication status	Published - 21 Mar 2017

Keywords

Journal Article

Access to Document

10.1073/pnas.1701219114

Cite this

Fumagalli, A., Drost, J., Suijkerbuijk, S. J. E., van Boxtel, R., de Ligt, J., Offerhaus, G. J., Begthel, H., Beerling, E., Tan, E. H., Sansom, O. J., Cuppen, E., Clevers, H., & van Rheenen, J. (2017). Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids. Proceedings of the National Academy of Sciences of the United States of America, 114(12), E2357-E2364. https://doi.org/10.1073/pnas.1701219114

@article{56b67f7d6bbc482b8ab9b891c0f1fcb3,

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.",

keywords = "Journal Article",

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

year = "2017",

month = mar,

day = "21",

doi = "10.1073/pnas.1701219114",

language = "English",

volume = "114",

pages = "E2357--E2364",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "12",

}

Fumagalli, A, Drost, J, Suijkerbuijk, SJE, van Boxtel, R, de Ligt, J, Offerhaus, GJ, Begthel, H, Beerling, E, Tan, EH, Sansom, OJ, Cuppen, E, Clevers, H & van Rheenen, J 2017, 'Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 12, pp. E2357-E2364. https://doi.org/10.1073/pnas.1701219114

Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids. / Fumagalli, Arianna; Drost, Jarno; Suijkerbuijk, Saskia J E et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 12, 21.03.2017, p. E2357-E2364.

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

TY - JOUR

T1 - Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids

AU - Fumagalli, Arianna

AU - Drost, Jarno

AU - Suijkerbuijk, Saskia J E

AU - van Boxtel, Ruben

AU - de Ligt, Joep

AU - Offerhaus, George Johan

AU - Begthel, Harry

AU - Beerling, Evelyne

AU - Tan, Ee Hong

AU - Sansom, Owen J

AU - Cuppen, Edwin

AU - Clevers, Hans

AU - van Rheenen, Jacco

PY - 2017/3/21

Y1 - 2017/3/21

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.

KW - Journal Article

U2 - 10.1073/pnas.1701219114

DO - 10.1073/pnas.1701219114

M3 - Article

C2 - 28270604

SN - 0027-8424

VL - 114

SP - E2357-E2364

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

IS - 12

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this