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Article: Targeting tumor lineage plasticity in hepatocellular carcinoma using an anti-CLDN6 antibody-drug conjugate

TitleTargeting tumor lineage plasticity in hepatocellular carcinoma using an anti-CLDN6 antibody-drug conjugate
Authors
Issue Date2021
PublisherAmerican Association for the Advancement of Science. The Journal's web site is located at http://www.sciencemag.org/marketing/stm/
Citation
Science Translational Medicine, 2021, v. 13 n. 579, p. article no. eabb6282 How to Cite?
AbstractTumor 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.
Persistent Identifierhttp://hdl.handle.net/10722/297151
ISSN
2015 SCImago Journal Rankings: 8.931
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorKong, FE-
dc.contributor.authorLi, GM-
dc.contributor.authorTang, YQ-
dc.contributor.authorXi, SY-
dc.contributor.authorLoong, JHC-
dc.contributor.authorLi, MM-
dc.contributor.authorLi, HL-
dc.contributor.authorCheng, W-
dc.contributor.authorZhu, WJ-
dc.contributor.authorMo, JQ-
dc.contributor.authorGong, YF-
dc.contributor.authorTang, H-
dc.contributor.authorZhao, Y-
dc.contributor.authorZhang, Y-
dc.contributor.authorMa, S-
dc.contributor.authorGuan, XY-
dc.contributor.authorMa, NF-
dc.contributor.authorXie, MB-
dc.contributor.authorLiu, M-
dc.date.accessioned2021-03-08T07:14:53Z-
dc.date.available2021-03-08T07:14:53Z-
dc.date.issued2021-
dc.identifier.citationScience Translational Medicine, 2021, v. 13 n. 579, p. article no. eabb6282-
dc.identifier.issn1946-6242-
dc.identifier.urihttp://hdl.handle.net/10722/297151-
dc.description.abstractTumor 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.-
dc.languageeng-
dc.publisherAmerican Association for the Advancement of Science. The Journal's web site is located at http://www.sciencemag.org/marketing/stm/-
dc.relation.ispartofScience Translational Medicine-
dc.rightsScience Translational Medicine. Copyright © American Association for the Advancement of Science.-
dc.rightsThis is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in [Science Journal Title] on [Volume number and date], DOI: [insert DOI number].-
dc.titleTargeting tumor lineage plasticity in hepatocellular carcinoma using an anti-CLDN6 antibody-drug conjugate-
dc.typeArticle-
dc.identifier.emailMa, S: stefma@hku.hk-
dc.identifier.emailGuan, XY: xyguan@hku.hk-
dc.identifier.authorityMa, S=rp00506-
dc.identifier.authorityGuan, XY=rp00454-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1126/scitranslmed.abb6282-
dc.identifier.pmid33536280-
dc.identifier.hkuros321584-
dc.identifier.volume13-
dc.identifier.issue579-
dc.identifier.spagearticle no. eabb6282-
dc.identifier.epagearticle no. eabb6282-
dc.identifier.isiWOS:000617689900003-
dc.publisher.placeUnited States-

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