RÉSUMÉ
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.
Sujet(s)
Antinéoplasiques , Carcinome hépatocellulaire , Immunoconjugués , Tumeurs du foie , Antinéoplasiques/pharmacologie , Carcinome hépatocellulaire/traitement médicamenteux , Lignée cellulaire tumorale , Prolifération cellulaire , Résistance aux médicaments antinéoplasiques , Humains , Immunoconjugués/usage thérapeutique , Tumeurs du foie/traitement médicamenteux , Récidive tumorale locale , Sorafénib/pharmacologie , Sorafénib/usage thérapeutiqueRÉSUMÉ
BACKGROUND: Loss of terminal differentiation markers and gain of stem cell-like properties are a major hallmark of cancer malignant progression. Identification of novel biomarkers representing tumor developmental progeny and predictive of patients' prognosis would greatly benefit clinical cancer management. METHODS: Human embryonic stem cells were induced to differentiate into hepatocytes along hepatic lineages. Transcriptomic data from different liver developmental stages were analyzed combining with the RNA-seq data from The Cancer Genome Atlas (TCGA) project. Kaplan-Meier survival analysis and Cox regression analyses were used to analyze the clinical significance in HCC patients. RESULTS: A shifted expression pattern of claudin (CLDN) family genes were identified to be closely associated with liver development and tumor progression. Claudins with hepatic features were found to be significantly down-regulated and predicted better prognosis in HCC patients. Conversely, another set of claudins with embryonic stem cell features were found to be significantly up-regulated and predicted worse prognosis in HCC patients. A claudin signature score system was further established by combining the two sets of claudin genes. The newly established claudins signature could robustly predict HCC patients' prognosis in the training, testing, and independent validation cohorts. CONCLUSIONS: In the present study, we developed a novel embryonic developmental claudins signature to monitor the extent of tumor dedifferentiation in HCC from an in vitro hepatocyte differentiation model. The claudins signature might present a great potential in predicting prognostic significance in HCC as cell surface biomarkers, and provide novel therapeutic targets for precision oncology further in the clinic.
Sujet(s)
Carcinome hépatocellulaire/diagnostic , Claudines/métabolisme , Hépatocytes/métabolisme , Tumeurs du foie/diagnostic , Marqueurs biologiques tumoraux/métabolisme , Carcinome hépatocellulaire/mortalité , Chine , Femelle , Régulation de l'expression des gènes tumoraux , Humains , Estimation de Kaplan-Meier , Tumeurs du foie/métabolisme , Tumeurs du foie/mortalité , Mâle , Pronostic , Modèles des risques proportionnelsRÉSUMÉ
Clinical observation of the association between cancer aggressiveness and embryonic development stage implies the importance of developmental signals in cancer initiation and therapeutic resistance. However, the dynamic gene expression during organogenesis and the master oncofetal drivers are still unclear, which impeded the efficient elimination of poor prognostic tumors, including human hepatocellular carcinoma (HCC). In this study, human embryonic stem cells were induced to differentiate into adult hepatocytes along hepatic lineages to mimic liver development in vitro. Combining transcriptomic data from liver cancer patients with the hepatocyte differentiation model, the active genes derived from different hepatic developmental stages and the tumor tissues were selected. Bioinformatic analysis followed by experimental assays was used to validate the tumor subtype-specific oncofetal signatures and potential therapeutic values. Hierarchical clustering analysis revealed the existence of two subtypes of liver cancer with different oncofetal properties. The gene signatures and their clinical significance were further validated in an independent clinical cohort and The Cancer Genome Atlas database. Upstream activator analysis and functional screening further identified E2F1 and SMAD3 as master transcriptional regulators. Small-molecule inhibitors specifically targeting the oncofetal drivers extensively down-regulated subtype-specific developmental signaling and inhibited tumorigenicity. Liver cancer cells and primary HCC tumors with different oncofetal properties also showed selective vulnerability to their specific inhibitors. Further precise targeting of the tumor initiating steps and driving events according to subtype-specific biomarkers might eliminate tumor progression and provide novel therapeutic strategy.
Sujet(s)
Marqueurs biologiques tumoraux/métabolisme , Carcinome hépatocellulaire/génétique , Régulation de l'expression des gènes au cours du développement , Régulation de l'expression des gènes tumoraux , Hépatocytes/anatomopathologie , Tumeurs du foie/génétique , Aminopyridines/pharmacologie , Aminopyridines/usage thérapeutique , Animaux , Marqueurs biologiques tumoraux/antagonistes et inhibiteurs , Carcinome hépatocellulaire/mortalité , Carcinome hépatocellulaire/anatomopathologie , Carcinome hépatocellulaire/chirurgie , Différenciation cellulaire/effets des médicaments et des substances chimiques , Différenciation cellulaire/génétique , Lignée cellulaire , Transformation cellulaire néoplasique/effets des médicaments et des substances chimiques , Transformation cellulaire néoplasique/génétique , Études de cohortes , Survie sans rechute , Facteur de transcription E2F1/antagonistes et inhibiteurs , Facteur de transcription E2F1/métabolisme , Femelle , Analyse de profil d'expression de gènes , Hépatectomie , Cellules souches embryonnaires humaines , Humains , Hydroxyquinoléines/pharmacologie , Hydroxyquinoléines/usage thérapeutique , Isoquinoléines/pharmacologie , Isoquinoléines/usage thérapeutique , Estimation de Kaplan-Meier , Foie/croissance et développement , Foie/anatomopathologie , Foie/chirurgie , Tumeurs du foie/mortalité , Tumeurs du foie/anatomopathologie , Tumeurs du foie/chirurgie , Mâle , Souris , Adulte d'âge moyen , Pronostic , Pyridines/pharmacologie , Pyridines/usage thérapeutique , Pyrroles/pharmacologie , Pyrroles/usage thérapeutique , Transduction du signal/génétique , Protéine Smad-3/antagonistes et inhibiteurs , Protéine Smad-3/métabolisme , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
BACKGROUND: Many studies confirm that anatomical resection was associated with favorable oncologic outcomes for patients with HCC who had preserved as much of the remnant liver tissue as possible.1,2 In recent years, laparoscopic liver resection has been widely extended from minor resection to complex hepatectomy,3 However, surgery on tumors located in the posterosuperior segment remains a demanding procedure regardless of the extent of resection.4 Laparoscopic anatomical segment VII resection has one of the highest difficulty scores based on the tumor location due to poor accessibility, hard to exposure, and difficulty in obtaining sufficient surgical margins.5,6 Here, we report a totally laparoscopic anatomical VII resection using the Glissonian approach with indocyanine green dye fluorescence. METHODS: A 74-year-old man with a body mass index of 31.9 kg/m2 suffered from HBV-related cirrhosis was admitted to our institution. The preoperative Gd-EOB-DTPA MRI showed a 2.7-cm HCC located in segment VIII. The preoperative AFP is 3431 ng/ml. A true anatomical segmentectomy was performed by using selective occlusion of segment VII Glissonian pedicle, which was identified from the liver hilum. Indocyanine green (ICG) dye demarcation was used as a guidance during parenchymal transection. RESULTS: The operative time was 270 min with an estimated blood loss of 200 mL. The postoperative course was uneventful. Drainage tube was pulled out on the fourth day. The pathology confirmed the diagnosis of hepatocellular carcinoma and the surgical margin was negative. The patient was discharged on the 8th day after operation. CONCLUSIONS: Totally laparoscopic anatomical segment VII resection is a technically challenging operation. Advanced laparoscopic skills are necessary to complete such a difficult procedure safely. Glissonian approach and ICG fluorescence imaging guide parenchyma resection could be help.