title: Comprehensive models of human primary and metastatic colorectal tumors in immunodeficient and immunocompetent mice by chemokine targeting.
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.
authors.affiliation: 1] Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA. [2] Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Huanhuan Joyce
authors.initials: HJ
authors.lastname: Chen
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, New York, New York, USA.
authors.forename: Harry
authors.initials: H
authors.lastname: Hou
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Myra
authors.initials: M
authors.lastname: Arcilla
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Rakhilin
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA.
authors.forename: Daniel J
authors.identifier: 0000000219458236
authors.initials: DJ
authors.lastname: Joe
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA.
authors.forename: Jiahn
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA.
authors.forename: Poornima
authors.initials: P
authors.lastname: Gadamsetty
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Milsom
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Govind
authors.initials: G
authors.lastname: Nandakumar
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Randy
authors.initials: R
authors.lastname: Longman
authors.affiliation: Department of Healthcare Policy and Research, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Xi Kathy
authors.identifier: 000000028942439X
authors.initials: XK
authors.lastname: Zhou
authors.affiliation: Department of Pathology, University of California, Irvine, Irvine, California, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Edwards
authors.affiliation: School of Electrical and Computer Engineering, Cornell University, Ithaca, New York, USA.
authors.forename: Jonlin
authors.initials: J
authors.lastname: Chen
authors.affiliation: School of Electrical and Computer Engineering, Cornell University, Ithaca, New York, USA.
authors.forename: Kai Yuan
authors.initials: KY
authors.lastname: Chen
authors.affiliation: 1] Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA. [2] School of Electrical and Computer Engineering, Cornell University, Ithaca, New York, USA.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Bu
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA.
authors.forename: Yitian
authors.initials: Y
authors.lastname: Xu
authors.affiliation: College of Veterinary Medicine and Biological Sciences, Cornell University, Ithaca, New York, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Munroe
authors.affiliation: College of Veterinary Medicine and Biological Sciences, Cornell University, Ithaca, New York, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Abratte
authors.affiliation: College of Veterinary Medicine and Biological Sciences, Cornell University, Ithaca, New York, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Miller
authors.affiliation: 1] Department of Medicine, Weill Cornell Medical College, New York, New York, USA. [2] Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Zeynep H
authors.identifier: 0000000273642202
authors.initials: ZH
authors.lastname: Gümüş
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Shuler
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Nishimura
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, New York, New York, USA.
authors.forename: Winfried
authors.initials: W
authors.lastname: Edelmann
authors.affiliation: 1] Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA. [2] School of Electrical and Computer Engineering, Cornell University, Ithaca, New York, USA.
authors.forename: Xiling
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Lipkin
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000473:pathology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000556:secondary; D051379:Mice; D009362:Neoplasm Metastasis; D054388:Receptors, CCR / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics*; D051880:Receptors, Notch / Q000096:biosynthesis; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: C119309:CC chemokine receptor 9; C442333:DKK4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D054388:Receptors, CCR; D051880:Receptors, Notch