Letter | Published:

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

Nature Biotechnology volume 35, pages 577582 (2017) | Download Citation

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.

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Acknowledgements

We thank D. Grace, S. Tian, and M. Taylor for technical assistance with animal colonies, other members of the Lowe laboratory for advice and discussions, J. Shia for assistance with histopathology, M. Gollub for assistance with interpreting MRI studies, and C. LeKaye, M. Lupu, and D. Winkleman for their technical support. We also thank members of the Englander Institute for Precision Medicine Organoid Platform, T. McNary, Y. Churakova, and C. Cheung. This work was supported by grants from the Starr Cancer Consortium (I7-A771, to M.A.R. and H.B.; and I8-A8-030 to. S.W.L. and L.E.D.), the Department of Defense (PC121341; to H.B.), and a Damon Runyon Cancer Research Foundation-Gordon Family Clinical Investigator Award (CI-67-13; to H.B.). This work was supported by grants from the NIH (U54 OD020355-01, R01 CA195787-01 and P30 CA008748). K.P.O'R. is supported by an F30 Award from the NIH/NCI (1CA200110-01A1). T.B. was supported by the MSKCC Single-Cell Sequencing Initiative, The William and Joyce O'Neil Research Fund. K.P.O'R. and E.M.S. were supported by a Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the National Institutes of Health under award number T32GM07739 to the Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program. P.B.R. is supported by a K12 Paul Calebresi Career Development Award for Clinical Oncology (CA 187069). L.E.D. was supported by a K22 Career Development Award from the NCI/NIH (CA 181280-01). Animal imaging studies were supported by the NIH Small-Animal Imaging Research Program (SAIRP), R24 CA83084; NIH Center Grant, P30 CA08748; NIH Prostate SPORE, P50-CA92629. S.W.L. is the Geoffrey Beene Chair of Cancer Biology and an Investigator of the Howard Hughes Medical Institute.

Author information

Affiliations

  1. Weill Cornell Medicine/Rockefeller University/Sloan Kettering Tri-Institutional MD-PhD Program, New York, New York, USA.

    • Kevin P O'Rourke
    •  & Emma M Schatoff
  2. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Kevin P O'Rourke
    • , Evangelia Loizou
    • , Geulah Livshits
    • , Timour Baslan
    • , Eusebio Manchado
    • , Janelle Simon
    • , Paul B Romesser
    •  & Scott W Lowe
  3. Weill Cornell Graduate School of Medical Sciences, New York, New York, USA.

    • Evangelia Loizou
    •  & Teng Han
  4. Meyer Cancer Center, Hematology & Medical Oncology Division, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.

    • Emma M Schatoff
    • , Benjamin Leach
    • , Teng Han
    • , Chantal Pauli
    • , Himisha Beltran
    • , Mark A Rubin
    •  & Lukas E Dow
  5. Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Paul B Romesser
  6. Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, New York, USA.

    • Chantal Pauli
    • , Himisha Beltran
    •  & Mark A Rubin
  7. Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Scott W Lowe

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Contributions

K.P.O'R., L.E.D., and S.W.L. conceived the project. K.P.O'R., designed, performed and analyzed experiments, and wrote the paper. E.L., G.L., E.M.S., T.B., E.M., J.S., P.R., B.L., T.H., C.P., H.B., and M.A.R. provided reagents, performed or analyzed experiments. L.E.D. and S.W.L supervised experiments, analyzed data, and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Lukas E Dow or Scott W Lowe.

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    Supplementary Text and Figures

    Supplementary Figures 1–15

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    Supplementary Table 1

    Summary of the orthotopic engraftment approaches.

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    Supplementary Video

    Organoid transplant procedure

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DOI

https://doi.org/10.1038/nbt.3837

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