Kong, Fan-En, Li, Guang-Meng, Tang, Yun-Qiang, Xi, Shao-Yan, Loong, Jane Ho Chun, Li, Mei-Mei, Li, Hao-Long, Cheng, Wei ORCID: 0000-0002-0088-7209, Zhu, Wen-Jie, Mo, Jia-Qiang, Gong, Yuan-Feng, Tang, Hui, Zhao, Yue, Zhang, Yan, Ma, Stephanie, Guan, Xin-Yuan, Ma, Ning-Fang, Xie, Mao-Bin and Liu, Ming (2021). Targeting tumor lineage plasticity in hepatocellular carcinoma using an anti-CLDN6 antibody-drug conjugate. Sci. Transl. Med., 13 (579). WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE. ISSN 1946-6242

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Abstract

Tumor lineage plasticity is emerging as a critical mechanism of therapeutic resistance and tumor relapse. Highly plastic tumor cells can undergo phenotypic switching to a drug-tolerant state to avoid drug toxicity. Here, we investigate the transmembrane tight junction protein Claudin6 (CLDN6) as a therapeutic target related to lineage plasticity for hepatocellular carcinoma (HCC). CLDN6 was highly expressed in embryonic stem cells but markedly decreased in normal tissues. Reactivation of CLDN6 was frequently observed in HCC tumor tissues as well as in premalignant lesions. Functional assays indicated that CLDN6 is not only a tumor-associated antigen but also conferred strong oncogenic effects in HCC. Overexpression of CLDN6 induced phenotypic shift of HCC cells from hepatic lineage to biliary lineage, which was more refractory to sorafenib treatment. The enhanced tumor lineage plasticity and cellular identity change were potentially induced by the CLDN6/TJP2 (tight junction protein 2)/ YAP1 (Yes-associated protein 1) interacting axis and further activation of the Hippo signaling pathway. A de novo anti-CLDN6 monoclonal antibody conjugated with cytotoxic agent (Mertansine) DM1 (CLDN6-DM1) was developed. Preclinical data on both HCC cell lines and primary tumors showed the potent antitumor efficiency of CLDN6-DM1 as a single agent or in combination with sorafenib in HCC treatment.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Kong, Fan-EnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, Guang-MengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tang, Yun-QiangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Xi, Shao-YanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loong, Jane Ho ChunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, Mei-MeiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, Hao-LongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cheng, WeiUNSPECIFIEDorcid.org/0000-0002-0088-7209UNSPECIFIED
Zhu, Wen-JieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mo, Jia-QiangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gong, Yuan-FengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tang, HuiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhao, YueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhang, YanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ma, StephanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guan, Xin-YuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ma, Ning-FangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Xie, Mao-BinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, MingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-592684
DOI: 10.1126/scitranslmed.abb6282
Journal or Publication Title: Sci. Transl. Med.
Volume: 13
Number: 579
Date: 2021
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
Place of Publication: WASHINGTON
ISSN: 1946-6242
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HIPPO PATHWAY; STEM-CELLS; DOUBLE-BLIND; ORGAN SIZE; LIVER; YAP; RESISTANCE; SORAFENIB; HETEROGENEITY; INHIBITIONMultiple languages
Cell Biology; Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/59268

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