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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 HJoyce, Sun J, Huang Z, Hou H, Arcilla M, Rakhilin N, Joe DJ, Choi J, Gadamsetty P, Milsom J, Nandakumar G, Longman R, Zhou XKathy, Edwards R, Chen J, Chen KYuan, Bu P, Wang L, Xu Y, Munroe R, Abratte C, Miller AD, Gümüş ZH, Shuler M, Nishimura N, Edelmann W, Shen X, Lipkin SM
JournalNat Biotechnol
Volume33
Issue6
Pagination656-60
Date Published2015 Jun
ISSN1546-1696
KeywordsAnimals, Blastocyst, Cell Line, Tumor, Colorectal Neoplasms, Disease Models, Animal, Gene Expression Regulation, Neoplastic, Humans, Intercellular Signaling Peptides and Proteins, Liver Neoplasms, Experimental, Mice, Neoplasm Metastasis, Receptors, CCR, Receptors, Notch, Signal Transduction, Xenograft Model Antitumor Assays
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
Alternate JournalNat. Biotechnol.
PubMed ID26006007
PubMed Central IDPMC4532544
Grant ListUH2 TR000516 / TR / NCATS NIH HHS / United States
R01 CA098626 / CA / NCI NIH HHS / United States
UL1 RR024996 / RR / NCRR NIH HHS / United States
R01 GM114254 / GM / NIGMS NIH HHS / United States
2UL1-RR024996 / RR / NCRR NIH HHS / United States
R01 GM095990 / GM / NIGMS NIH HHS / United States
R01 CA076329 / CA / NCI NIH HHS / United States
CA098626 / CA / NCI NIH HHS / United States
K08 DK099381 / DK / NIDDK NIH HHS / United States
UL1 TR001414 / TR / NCATS NIH HHS / United States
R56 CA098626 / CA / NCI NIH HHS / United States
UH2TR000516 / TR / NCATS NIH HHS / United States
P30 CA013330 / CA / NCI NIH HHS / United States
UL1 TR000457 / TR / NCATS NIH HHS / United States