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Transplantation of engineered organoids enables rapid generation of metastatic mouse models of colorectal cancer.

TitleTransplantation of engineered organoids enables rapid generation of metastatic mouse models of colorectal cancer.
Publication TypeJournal Article
Year of Publication2017
AuthorsO'Rourke KP, Loizou E, Livshits G, Schatoff EM, Baslan T, Manchado E, Simon J, Romesser PB, Leach B, Han T, Pauli C, Beltran H, Rubin MA, Dow LE, Lowe SW
JournalNat Biotechnol
Volume35
Issue6
Pagination577-582
Date Published2017 Jun
ISSN1546-1696
Abstract

Colorectal cancer (CRC) is a leading cause of death in the developed world, yet facile preclinical models that mimic the natural stages of CRC progression are lacking. Through the orthotopic engraftment of colon organoids we describe a broadly usable immunocompetent CRC model that recapitulates the entire adenoma-adenocarcinoma-metastasis axis in vivo. The engraftment procedure takes less than 5 minutes, shows efficient tumor engraftment in two-thirds of mice, and can be achieved using organoids derived from genetically engineered mouse models (GEMMs), wild-type organoids engineered ex vivo, or from patient-derived human CRC organoids. In this model, we describe the genotype and time-dependent progression of CRCs from adenocarcinoma (6 weeks), to local disseminated disease (11-12 weeks), and spontaneous metastasis (>20 weeks). Further, we use the system to show that loss of dysregulated Wnt signaling is critical for the progression of disseminated CRCs. Thus, our approach provides a fast and flexible means to produce tailored CRC mouse models for genetic studies and pre-clinical investigation.

DOI10.1038/nbt.3837
Alternate JournalNat. Biotechnol.
PubMed ID28459450
PubMed Central IDPMC5462850
Grant ListF30 CA200110 / CA / NCI NIH HHS / United States