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

2021 ◽  
Vol 13 (579) ◽  
pp. eabb6282
Author(s):  
Fan-En Kong ◽  
Guang-Meng Li ◽  
Yun-Qiang Tang ◽  
Shao-Yan Xi ◽  
Jane Ho Chun Loong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tight Junction ◽  
Single Agent ◽  
Embryonic Stem ◽  
Tight Junction Protein ◽  
Premalignant Lesions ◽  
Phenotypic Switching ◽  
Primary Tumors ◽  
Sorafenib Treatment ◽  
Junction Protein

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.

scholarly journals The Tight-Junction Protein Claudin-6 Induces Epithelial Differentiation from Mouse F9 and Embryonic Stem Cells

PLoS ONE ◽  
2013 ◽  
Vol 8 (10) ◽  
pp. e75106 ◽  
Author(s):  
Kotaro Sugimoto ◽  
Naoki Ichikawa-Tomikawa ◽  
Seiro Satohisa ◽  
Yushi Akashi ◽  
Risa Kanai ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Tight Junction ◽  
Embryonic Stem ◽  
Epithelial Differentiation ◽  
Tight Junction Protein ◽  
Junction Protein

scholarly journals Hepatocellular carcinoma associated with tight-junction protein 2 deficiency

Hepatology ◽  
2015 ◽  
Vol 62 (6) ◽  
pp. 1914-1916 ◽  
Author(s):  
Shengmei Zhou ◽  
Paula M. Hertel ◽  
Milton J. Finegold ◽  
Larry Wang ◽  
Nanda Kerkar ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tight Junction ◽  
Tight Junction Protein ◽  
Junction Protein

Paediatric hepatocellular carcinoma in tight junction protein 2 (TJP2) deficiency

2017 ◽  
Vol 471 (5) ◽  
pp. 679-683 ◽  
Author(s):  
Mukul Vij ◽  
Naresh P. Shanmugam ◽  
Mettu Srinivas Reddy ◽  
Srinivas Sankaranarayanan ◽  
Mohamed Rela
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tight Junction ◽  
Tight Junction Protein ◽  
Junction Protein

scholarly journals Expression of Tight Junction Protein Claudin-5 in Tumor Vessels and Sinusoidal Endothelium in Patients With Hepatocellular Carcinoma

2008 ◽  
Vol 147 (1) ◽  
pp. 123-131 ◽  
Author(s):  
Takanori Sakaguchi ◽  
Shohachi Suzuki ◽  
Hiroyuki Higashi ◽  
Keisuke Inaba ◽  
Satoshi Nakamura ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tight Junction ◽  
Tight Junction Protein ◽  
Tumor Vessels ◽  
Junction Protein ◽  
Sinusoidal Endothelium

Impact of Tight Junction Protein ZO-1 and TWIST Expression on Postoperative Survival of Patients with Hepatocellular Carcinoma

2016 ◽  
Vol 34 (6) ◽  
pp. 702-707 ◽  
Author(s):  
Tomoyuki Nagai ◽  
Tokuzo Arao ◽  
Kazuto Nishio ◽  
Kazuko Matsumoto ◽  
Satoru Hagiwara ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tight Junction ◽  
Hepatic Resection ◽  
Cancer Progression ◽  
Critical Role ◽  
Tight Junction Protein ◽  
Mesenchymal Transition ◽  
Junction Protein ◽  
Twist Expression ◽  
The Impact

Background: Epithelial-mesenchymal transition (EMT) is considered to play a critical role in cancer progression and metastasis. However, the impact of EMT on the prognosis of hepatocellular carcinoma (HCC) is still elusive. In this study, we examined the relationship between the expression of EMT markers and recurrence-free survival (RFS) and overall survival (OS) in HCC patients after hepatic resection. Summary: The mRNA expression of 15 genes related to EMT was assessed by quantitative real-time polymerase chain reaction in cancerous tissues from 72 patients who underwent hepatic resection of HCC between January 2005 and December 2010 at our hospital. The upregulation of TWIST and the downregulation of tight junction protein ZO-1 (TJP1) were significantly associated with shorter RFS as well as OS. Increased levels of TWIST and decreased levels of TJP1 should be predictive markers for poor prognosis in patients with HCC after hepatectomy; those could serve as potential biomarkers for the treatment of HCC. Key Messages: A low level of TJP1 and high level of TWIST expression were prognostic factors predicting HCC after hepatic resection.

scholarly journals Polycystin-2 Activity Is Controlled by Transcriptional Coactivator with PDZ Binding Motif and PALS1-associated Tight Junction Protein

2010 ◽  
Vol 285 (44) ◽  
pp. 33584-33588 ◽  
Author(s):  
Kerstin Duning ◽  
Deike Rosenbusch ◽  
Marc A. Schlüter ◽  
Yuemin Tian ◽  
Karl Kunzelmann ◽  
...  
Keyword(s):  
Tight Junction ◽  
Tight Junction Protein ◽  
Binding Motif ◽  
Transcriptional Coactivator ◽  
Junction Protein

scholarly journals Endothelial-specific insulin receptor substrate-1 overexpression worsens neonatal hypoxic-ischemic brain injury via mTOR-mediated tight junction disassembly

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yi-Fang Tu ◽  
Si-Tse Jiang ◽  
Chi-Wu Chiang ◽  
Li-Ching Chen ◽  
Chao-Ching Huang
Keyword(s):  
Endothelial Cells ◽  
Brain Injury ◽  
Tight Junction ◽  
Insulin Receptor ◽  
Vascular Endothelial Cells ◽  
Tight Junction Protein ◽  
Insulin Receptor Substrate ◽  
Vascular Endothelial ◽  
Transgenic Rats ◽  
Junction Protein

AbstractHypoxic-ischemic (HI) encephalopathy is the major cause of mortality and disability in newborns. The neurovascular unit is a major target of acute and chronic brain injury, and therapies that protect simultaneously both neurons and vascular endothelial cells from neonatal HI injury are in demand. Insulin receptors and its key downstream molecule-insulin receptor substrate −1 (IRS-1) are potential neuroprotective targets and expressed both in neuron and endothelial cells. To investigate whether IRS-1 can act similarly in neurons and vascular endothelial cells in protecting neurovascular units and brain form HI injury, we found that neuron-specific IRS-1 transgenic rats showed reduced neurovascular injury and infarct volumes, whereas endothelial-specific IRS-1 transgenic rats showed increased blood-brain barrier (BBB) disruption and exaggerated neurovascular injury after neonatal HI brain injury. Endothelial-specific IRS-1 overexpression increased vascular permeability and disassembled the tight junction protein (zonula occludens-1) complex. Inhibition of mammalian target of rapamycin (mTOR) by rapamycin preserved tight junction proteins and attenuated BBB leakage and neuronal apoptosis after HI in the endothelial-specific IRS-1 transgenic pups. Together, our findings suggested that neuronal and endothelial IRS-1 had opposite effects on the neurovascular integrity and damage after neonatal HI brain injury and that endothelial IRS-1 worsens neurovascular integrity after HI via mTOR-mediated tight junction protein disassembly.

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