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

TitleComprehensive models of human primary and metastatic colorectal tumors in immunodeficient and immunocompetent mice by chemokine targeting.
Publication TypeJournal Article
Year of Publication2015
AuthorsChen, HJ, Sun, J, Huang, Z, Hou, H, Arcilla, M, Rakhilin, N, Joe, DJ, Choi, J, Gadamsetty, P, Milsom, J, Nandakumar, G, Longman, R, Zhou, XK, Edwards, R, Chen, J, Chen, KY, Bu, P, Wang, L, Xu, Y, Munroe, R, Abratte, C, Miller, AD, Gümüş, ZH, Shuler, M, Nishimura, N, Edelmann, W, Shen, X, and Lipkin, SM
JournalNature Biotechnology
Volume33
Issue6
Start Page656
Pagination656 - 660
Date Published06/2015
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.

DOI10.1038/nbt.3239
Short TitleNature Biotechnology