Comprehensive models of human primary and metastatic colorectal tumors in immunodeficient and immunocompetent mice by chemokine targeting

Huanhuan Joyce Chen, Jian Sun, Zhiliang Huang, Harry Hou, Myra Arcilla, Nikolai Rakhilin, Daniel J. Joe, Jiahn Choi, Poornima Gadamsetty, Jeff Milsom, Govind Nandakumar, Randy Longman, Xi Kathy Zhou, Robert Edwards, Jonlin Chen, Kai Yuan Chen, Pengcheng Bu, Lihua Wang, Yitian Xu, Robert MunroeChristian Abratte, Andrew D. Miller, Zeynep H. Gümüş, Michael Shuler, Nozomi Nishimura, Winfried Edelmann, Xiling Shen, Steven M. Lipkin

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Current orthotopic xenograft models of human colorectal cancer (CRC) require surgery and do not robustly form metastases in the liver, the most common site clinically. CCR9 traffics lymphocytes to intestine and colorectum. We engineered use of the chemokine receptor CCR9 in CRC cell lines and patient-derived cells to create primary gastrointestinal (GI) tumors in immunodeficient mice by tail-vein injection rather than surgery. The tumors metastasize inducibly and robustly to the liver. Metastases have higher DKK4 and NOTCH signaling levels and are more chemoresistant than paired subcutaneous xenografts. Using this approach, we generated 17 chemokine-targeted mouse models (CTMMs) that recapitulate the majority of common human somatic CRC mutations. We also show that primary tumors can be modeled in immunocompetent mice by microinjecting CCR9-expressing cancer cell lines into early-stage mouse blastocysts, which induces central immune tolerance. We expect that CTMMs will facilitate investigation of the biology of CRC metastasis and drug screening.

Original languageEnglish (US)
Pages (from-to)656-660
Number of pages5
JournalNature biotechnology
Volume33
Issue number6
DOIs
StatePublished - Jun 11 2015

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine
  • Biomedical Engineering

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  • Cite this

    Chen, H. J., Sun, J., Huang, Z., Hou, H., Arcilla, M., Rakhilin, N., Joe, D. J., Choi, J., Gadamsetty, P., Milsom, J., Nandakumar, G., Longman, R., Zhou, X. K., Edwards, R., Chen, J., Chen, K. Y., Bu, P., Wang, L., Xu, Y., ... Lipkin, S. M. (2015). Comprehensive models of human primary and metastatic colorectal tumors in immunodeficient and immunocompetent mice by chemokine targeting. Nature biotechnology, 33(6), 656-660. https://doi.org/10.1038/nbt.3239