Identifying tumor promoting genomic alterations in tumor-associated fibroblasts via retrovirus-insertional mutagenesis
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Lijie Rong1,2,3,*, Yangyang Bian1,*, Shubai Liu2,3,*, Xiaoman Liu2,3, Xiao Li2,3,**, Haiyang Liu2,3,4, Jinxue Zhou5, Jirun Peng6,7,8, Henghui Zhang9, Hongsong Chen9 and Zhihai Qin1,2,3
1Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, China
2Key Laboratory of Protein and Peptide Pharmaceuticals, Chinese Academy of Sciences-University of Tokyo, Beijing, 100101, China
3Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
4University of Chinese Academy of Sciences, Beijing, 100049, China
5Henan Tumor Hospital, Zhengzhou, 450008, China
6Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China
7Capital Medical University Clinical Cancer Center, Beijing, 100038, China
8Ninth Clinical Medical College of Peking University, Beijing, 100038, China
9Peking University People's Hospital, Peking University Hepatology Institute, Beijing, 100044, China
*These authors have contributed equally to this work
**Current Address: Beijing Institute For Drug Control, Beijing, 102206, China
Zhihai Qin, email: [email protected]
Keywords: Tumor-associated fibroblasts, retrovirus-insertional mutagenesis, tumor-promoting gene, co-injection model, Ttl
Received: July 04, 2017 Accepted: September 21, 2017 Published: October 16, 2017
Tumor-associated fibroblasts (TAFs) are often essential for solid tumor growth. However, few genetic or epigenetic alterations have been found in TAFs during the progression of solid tumors. Employing a tumor-stromal cell co-injection model, we adapted here retroviral-insertional mutagenesis to stromal cells to identify novel tumor-associated genes in TAFs. We successfully identified 20 gene candidates that might modulate tumor growth if altered in TAFs at genomic level. To validate our finding, the function of one of the candidate genes, tubulin tyrosine ligase (Ttl), was further studied in TAFs from fibrosarcoma, colon, breast and hepatocarcinoma. We demonstrated that down-regulated TTL expression in TAFs indeed promoted tumor growth in mice. Interestingly, decreased expression of TTL in tumor stromal cells also correlated with poor outcome in human colon carcinoma. Thus, the co-injection model of tumor cells with retrovirus-modified fibroblasts proved a valid method to identify tumor-modulating genes in TAFs, allowing for a deeper insight into the role of the stroma for tumor development.
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