Colorectal cancer (CRC) is a leading cause of cancer death. Current human CRC orthotopic xenograft models require survival surgery and do not robustly form tumors in liver, the most common site of metastasis in patients. Here, we use chemokine-targeting to develop cell line and primary patient-derived xenograft models that recapitulate the vast majority of common human somatic CRC mutations as primary gastrointestinal (GI) tumors in mice without requiring surgery. Importantly, we utilize early-stage mouse blastocyst microinjection techniques to extend this approach and model primary human CRCs in immunoproficient mouse hosts. Next, we show that primary GI tumors can inducibly and robustly metastasize to liver. Finally, we demonstrate that human CRC liver metastases in vivo have higher levels of DKK4 and NOTCH signaling and are more chemoresistant than paired sub-cutaneous xenografts. Overall, we anticipate that this experimental system can help improve our mechanistic understanding of human primary CRC progression to liver metastasis, and augment sub-cutaneous xenografts for pre-clinical drug screening.
Citation Format: Steven M. Lipkin, Huanhuan Joyce Chen, Jian Sun, Zhiliang Huang, Harry Hou, Myra Arcilla, Nikolai Rakhilin, Daniel Joe, Jiahn Choi, Poornima Gadamsetty, Jeff Milsom, Govind Nandakumar, Randy Longman, Kathy Zhou, Robert Edwards, Kai Yuan Chen, Pengcheng Bu, Lihua Wang, Yitian Xu, Robert Munroe, Christian Abratte, Andrew Miller, Zeynep Gümüş, Michael Shuler, Nozomi Nishimura, Winfried Edelmann, Xiling Shen. Chemokine-targeted models of human orthotopic colorectal cancer in immunocompetant mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2891. doi:10.1158/1538-7445.AM2015-2891