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

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Chen, 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; Lipkin, SM

Published Date

  • June 2015

Published In

Volume / Issue

  • 33 / 6

Start / End Page

  • 656 - 660

PubMed ID

  • 26006007

Electronic International Standard Serial Number (EISSN)

  • 1546-1696

International Standard Serial Number (ISSN)

  • 1087-0156

Digital Object Identifier (DOI)

  • 10.1038/nbt.3239

Language

  • eng