Colorectal cancer (CRC) is a leading cause of cancer death worldwide and 5-year survival for metastatic CRC is only ~15%. Immunotherapy is an important new approach to treat solid tumors. However, to date it appears largely ineffective against CRC, and the immune mechanisms underlying human CRC growth and metastasis are poorly understood. In part, this is because human CRC xenograft models could only be generated in immunodeficient mouse hosts because of xeno-rejection. We recently developed chemokine targeted mouse models (CTMM), a novel experimental approach to robustly model primary CRCs in the native GI micro- environment without requiring surgery. By using the Chemokine Receptor 9/ Chemokine 25 axis, CTMM traffics human CRC cells to form orthotopic tumors in the GI tract. Here, we describe an innovative combination of mouse ES cell technology and CTMM to generate human CRC-mouse chimeras, the first robust model of human orthotopic CRC in immunocompetent mouse hosts for mechanistic studies to address underlying tumor immunology and potential therapeutic targets in vivo. The overall goal of this application is to understand mechanisms of interaction between human CRC cells, tumor infiltrating immune cells, and the intestinal microbiota to promote orthotopic tumor growth in immunocompetent hosts.

Public Health Relevance

Colorectal cancer is a leading cause of cancer death worldwide and 5-year survival for metastatic CRC is only ~15%. Immunotherapy is an important new approach to treat solid tumors. However, to date it appears largely ineffective against colorectal cancer. In part, this is because mouse models studying human colorectal cancer models could only be performed in mice with impaired immune systems so they don't reject the human cells. Here, we describe an innovative technology to study human colorectal cancer cells in the colon of mice with an intact immune system. These experiments can lead to vaccines against cancer causing bacteria and drugs targeting specific immune signaling molecules to reduce colorectal cancer incidence.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA201829-01
Application #
9021980
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Daschner, Phillip J
Project Start
2016-08-01
Project End
2018-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Blander, J Magarian; Longman, Randy S; Iliev, Iliyan D et al. (2017) Regulation of inflammation by microbiota interactions with the host. Nat Immunol 18:851-860