JHEP Reports最新文献

{"title":"Hepatic stellate cell single cell atlas reveals a highly similar activation process across liver disease aetiologies","authors":"Vincent Merens ,&nbsp;Elisabeth Knetemann ,&nbsp;Elif Gürbüz ,&nbsp;Vincent De Smet ,&nbsp;Nouredin Messaoudi ,&nbsp;Hendrik Reynaert ,&nbsp;Stefaan Verhulst ,&nbsp;Leo A. van Grunsven","doi":"10.1016/j.jhepr.2024.101223","DOIUrl":"10.1016/j.jhepr.2024.101223","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The progression of chronic liver disease (CLD) is characterized by excessive extracellular matrix deposition, disrupting hepatic architecture and function. Upon liver injury, hepatic stellate cells (HSCs) differentiate towards myofibroblasts and become inflammatory, proliferative and fibrogenic. To date, it is still unclear whether HSC activation is driven by similar mechanisms in different aetiologies.</div></div><div><h3>Methods</h3><div>HSCs from multiple publicly available single-cell RNA-sequencing datasets were annotated and merged into a single-cell HSC activation atlas. Spheroid co-cultures of primary mouse hepatocytes/HSCs (n = 5) and ELISAs on patient plasma samples (n = 80) were performed to validate the mechanistic insight obtained from the HSC atlas.</div></div><div><h3>Results</h3><div>We established an HSC activation atlas in which HSCs are clearly divided into three distinct transcriptomic profiles: quiescent HSCs, initiatory HSCs and myofibroblasts. These transcriptomic profiles are present in each of the investigated mouse liver injury models as well as in human CLDs, indicating that HSC activation is a conserved process. This activation process is driven by a core set of transcription factors independent of liver injury or species. Furthermore, we reveal novel ligands associated with activation of HSCs in multiple liver injury models and validate the profibrotic effect of parathyroid hormone. Finally, we identify <em>COLEC10</em> as a conserved marker for quiescent HSCs and a biomarker of liver fibrosis in patients with different CLDs (<em>p &lt;</em>0.0001).</div></div><div><h3>Conclusions</h3><div>We reveal unexpected similarities in the regulatory mechanisms of HSCs across diverse liver injury settings and species. The HSC activation atlas has the potential to provide novel insights into liver fibrosis and steer novel treatment options.</div></div><div><h3>Impact and implications:</h3><div>This study establishes a single-cell atlas of hepatic stellate cells across various liver injuries, highlighting a conserved activation process between different injuries and across species. The discovery of novel activating ligands and the biomarker COLEC10 in human plasma could be used to enhance diagnostic and therapeutic strategies. Additionally, the conserved activation process supports the use of any mouse model for mechanistic studies and testing of new anti-fibrotic compounds, streamlining preclinical research efforts.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 1","pages":"Article 101223"},"PeriodicalIF":9.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The first year of the new Editorial Team of JHEP Reports","authors":"Xavier Forns ,&nbsp;Josep M. Llovet","doi":"10.1016/j.jhepr.2024.101292","DOIUrl":"10.1016/j.jhepr.2024.101292","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 1","pages":"Article 101292"},"PeriodicalIF":9.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770347/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biliary atresia susceptibility gene EFEMP1 regulates extrahepatic bile duct elastic fiber formation and mechanics","authors":"Kapish Gupta ,&nbsp;Jessica Llewellyn ,&nbsp;Emilia Roberts ,&nbsp;Chengyang Liu ,&nbsp;Ali Naji ,&nbsp;Richard K. Assoian ,&nbsp;Rebecca G. Wells","doi":"10.1016/j.jhepr.2024.101215","DOIUrl":"10.1016/j.jhepr.2024.101215","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>EGF-containing fibulin extracellular matrix protein 1 (EFEMP1, also called fibulin-3) is an extracellular matrix protein linked in a genome-wide association study to biliary atresia, a fibrotic disease of the neonatal extrahepatic bile duct. Fibulin-3 is deposited in most tissues and <em>Efemp1</em> null mice have decreased elastic fibers in visceral fascia; however, fibulin-3 does not have a role in the development of large elastic fibers and its overall function in the extrahepatic bile ducts remains unclear.</div></div><div><h3>Methods</h3><div>We used staining and histology to define the amount and organization of key extracellular matrix components in the extrahepatic bile ducts. We also repurposed pressure myography, a technique heretofore applied to the vasculature, to determine the contribution of elastin and fibulin-3 to extrahepatic bile duct mechanics. We examined extrahepatic bile duct structure and mechanics in three models: neonatal <em>vs.</em> adult rat ducts (n = 6 each), elastase-treated adult rat ducts (n = 6-7 each), and <em>Efemp1</em>^+/- <em>vs.</em> wild-type mouse ducts (n = 6 each).</div></div><div><h3>Results</h3><div>We demonstrated that fibulin-3 is expressed in the submucosa of both neonatal and adult mouse, rat and human extrahepatic bile ducts and that, in adult <em>Efemp1</em>^+/- mouse ducts, elastin organization into fibers is decreased by approximately half. Pressure myography showed that <em>Efemp1</em>^+/- ducts have altered mechanics compared to control ducts, with <em>Efemp1</em>^+/- ducts displaying significant stretch compared to controls (<em>p =</em> 0.0376); these changes in stretch are similar to those observed in elastase-treated <em>vs</em>. normal ducts (<em>p</em> &lt;0.0001) and in neonatal ducts <em>vs.</em> adult ducts (<em>p</em> &lt;0.0001).</div></div><div><h3>Conclusion</h3><div>Fibulin-3 has an important role in the formation of elastic fibers and the mechanical properties of the extrahepatic bile duct. This provides functional relevance for the biliary atresia susceptibility gene EFEMP1.</div></div><div><h3>Impact and implications:</h3><div>The gene EFEMP1 was found via a genome-wide association study to be a susceptibility gene for the neonatal disease biliary atresia. EFEMP1 encodes the protein fibulin-3, which regulates elastic fiber organization in the extrahepatic bile duct (EHBD), the major site of disease in biliary atresia. We showed that neonatal EHBDs as well as mice heterozygous for <em>Efemp1</em> have decreased numbers of elastic fibers, and that this alters EHBD mechanics. This work is important for understanding the mechanism of biliary atresia, in particular susceptibility to obstruction.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 1","pages":"Article 101215"},"PeriodicalIF":9.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11663959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct virologic trajectories in chronic hepatitis B identify heterogeneity in response to nucleos(t)ide analogue therapy","authors":"Tingyan Wang ,&nbsp;Cori Campbell ,&nbsp;Alexander J. Stockdale ,&nbsp;Stacy Todd ,&nbsp;Karl McIntyre ,&nbsp;Andrew Frankland ,&nbsp;Jakub Jaworski ,&nbsp;Ben Glampson ,&nbsp;Dimitri Papadimitriou ,&nbsp;Luca Mercuri ,&nbsp;Erik Mayer ,&nbsp;Christopher R. Jones ,&nbsp;Hizni Salih ,&nbsp;Gail Roadknight ,&nbsp;Stephanie Little ,&nbsp;Theresa Noble ,&nbsp;Kinga A. Várnai ,&nbsp;Cai Davis ,&nbsp;Ashley I. Heinson ,&nbsp;Michael George ,&nbsp;Philippa C. Matthews","doi":"10.1016/j.jhepr.2024.101229","DOIUrl":"10.1016/j.jhepr.2024.101229","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The dynamics of HBV viral load (VL) in patients with chronic hepatitis B (CHB) on nucleos(t)ide analogue (NA) treatment and its relationship with liver disease are poorly understood. We aimed to study longitudinal VL patterns and their associations with CHB clinical outcomes.</div></div><div><h3>Methods</h3><div>Utilising large scale, routinely collected electronic health records from six centres in England, collated by the National Institute for Health and Care Research Health Informatics Collaborative (NIHR HIC), we applied latent class mixed models to investigate VL trajectory patterns in adults receiving NA treatment. We assessed associations of VL trajectory with alanine transaminase, and with liver fibrosis/cirrhosis.</div></div><div><h3>Results</h3><div>We retrieved data from 1,885 adults on NA treatment (median follow-up 6.2 years, IQR 3.7–9.3 years), with 21,691 VL measurements (median 10 per patient, IQR 5–17). Five VL classes were identified from the derivation cohort (n = 1,367, discrimination: 0.93, entropy: 0.90): class 1 ‘long term suppression’ (n = 827, 60.5%), class 2 ‘timely virological suppression’ (n = 254, 18.6%), class 3 ‘persistent moderate viraemia’ (n = 140, 10.2%), class 4 ‘persistent high-level viraemia’ (n = 44, 3.2%), and class 5 ‘slow virological suppression’ (n = 102, 7.5%). The model demonstrated a discrimination of 0.93 and entropy of 0.88 for the validation cohort (n = 518). Alanine transaminase decreased variably over time in VL-suppressed groups (classes 1, 2, 5; all <em>p</em> &lt;0.001), but did not significantly improve in those with persistent viraemia (classes 3, 4). Patients in class 5 had twofold increased hazards of fibrosis/cirrhosis compared with class 1 (adjusted hazard ratio, 2.00; 95% CI, 1.33–3.02).</div></div><div><h3>Conclusions</h3><div>Heterogeneity exists in virological response to NA therapy in CHB patients, with over 20% showing potentially suboptimal responses. Slow virological suppression is associated with liver disease progression.</div></div><div><h3>Impact and implications:</h3><div>Treatment recommendations for people living with chronic hepatitis B virus (HBV) infection are becoming less stringent, meaning that more of the population will be eligible to receive therapy with nucleos(t)ide analogue agents. We explored outcomes of HBV treatment in a large UK dataset, describing different responses to treatment, and showing that the viral load is not completely suppressed after 1 year in about one in five cases, associated with an increased risk of liver complications. As treatment is rolled out more widely, patients and clinicians need to be aware of the potential for incomplete virologic responses. The findings can support the identification of high-risk individuals, improve early fibrosis and cirrhosis prediction, guide monitoring and preventive interventions, and support public health elimination goals.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 1","pages":"Article 101229"},"PeriodicalIF":9.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11664071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EASL Schools of Hepatology: Pioneering the flipped classroom model and blended learning in medical education","authors":"Francesco Negro ,&nbsp;Mounia Heddad Masson ,&nbsp;Ulrich Beuers","doi":"10.1016/j.jhepr.2024.101266","DOIUrl":"10.1016/j.jhepr.2024.101266","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 1","pages":"Article 101266"},"PeriodicalIF":9.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microwave ablation vs. single-needle radiofrequency ablation for the treatment of HCC up to 4 cm: A randomized-controlled trial","authors":"Katsutoshi Sugimoto ,&nbsp;Kento Imajo ,&nbsp;Hidekatsu Kuroda ,&nbsp;Go Murohisa ,&nbsp;Kazue Shiozawa ,&nbsp;Kentaro Sakamaki ,&nbsp;Takuya Wada ,&nbsp;Hirohito Takeuchi ,&nbsp;Kei Endo ,&nbsp;Tamami Abe ,&nbsp;Takashi Matsui ,&nbsp;Takahiro Murakami ,&nbsp;Masato Yoneda ,&nbsp;Atsushi Nakajima ,&nbsp;Shigehiro Kokubu ,&nbsp;Takao Itoi","doi":"10.1016/j.jhepr.2024.101269","DOIUrl":"10.1016/j.jhepr.2024.101269","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Radiofrequency ablation (RFA) is the standard treatment for small hepatocellular carcinoma (HCC), specifically for tumors &lt;3 cm in size and numbering fewer than three, excluding surgical candidates. Microwave ablation (MWA) is an innovative approach believed to have theoretical benefits over RFA; however, these advantages are yet to be empirically verified. Therefore, we evaluated and compared the effectiveness of MWA and RFA in managing HCC tumors up to 4 cm in size.</div></div><div><h3>Methods</h3><div>In this multicenter randomized controlled trial conducted across five centers in Japan, eligible participants had up to 4 tumors, each up to 4 cm in size, and were not considered for surgery. Patients were randomly assigned to undergo MWA or RFA. The primary outcome was the rate of local tumor progression (LTP), whereas secondary outcomes included overall survival (OS) and intra- and extrahepatic recurrence-free survival (RFS) at the end of the 2-year follow up.</div></div><div><h3>Results</h3><div>In total, 240 participants were screened from July 12, 2018, to December 7, 2021. Four participants were excluded: three did not meet inclusion criteria, and one died from an unknown cause during treatment. Consequently, 119 (130 lesions) and 117 (136 lesions) participants were treated with MWA and RFA, respectively. The proportion of lesions with LTP at the 2-year follow up was significantly lower in the MWA group (20 [16.4%] lesions) than in the RFA group (38 [30.4%] lesions) (risk ratio, 0.54; <em>p</em> = 0.007). OS and both intra- and extrahepatic RFS did not significantly differ between groups.</div></div><div><h3>Conclusions</h3><div>MWA is more effective than RFA in reducing local tumor progression for HCC tumors up to 4 cm. However, no differences were observed in OS and RFS.</div></div><div><h3>Impact and implications:</h3><div>While some randomized control trials (RCTs) have compared the efficacy of microwave ablation (MWA) and radiofrequency ablation (RFA) for small hepatocellular carcinoma (HCC), the superiority of MWA over RFA remains unverified despite its theoretical benefit. This study is the first to demonstrate the utility of MWA over single-needle RFA for patients with HCC, with a significant difference between the two groups in the proportion of lesions with local tumor progression after a 2-year follow up. Moreover, the two techniques were safe, with only two severe complications reported in the entire study cohort. Given that an RCT differs slightly from daily clinical situations, practical and anatomical criteria for selecting the optimal technique on a lesion-by-lesion basis are required.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 1","pages":"Article 101269"},"PeriodicalIF":9.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11719385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial Board page","authors":"","doi":"10.1016/S2589-5559(24)00320-3","DOIUrl":"10.1016/S2589-5559(24)00320-3","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 1","pages":"Article 101316"},"PeriodicalIF":9.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143160661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor burden with AFP improves survival prediction for TACE-treated patients with HCC: An international observational study☆","authors":"Dongdong Xia ,&nbsp;Wei Bai ,&nbsp;Qiuhe Wang ,&nbsp;Jin Wook Chung ,&nbsp;Xavier Adhoute ,&nbsp;Roman Kloeckner ,&nbsp;Hui Zhang ,&nbsp;Yong Zeng ,&nbsp;Pimsiri Sripongpun ,&nbsp;Chunhui Nie ,&nbsp;Seung Up Kim ,&nbsp;Ming Huang ,&nbsp;Wenhao Hu ,&nbsp;Xiangchun Ding ,&nbsp;Guowen Yin ,&nbsp;Hailiang Li ,&nbsp;Hui Zhao ,&nbsp;Jean-Pierre Bronowicki ,&nbsp;Jing Li ,&nbsp;Jiaping Li ,&nbsp;Guohong Han","doi":"10.1016/j.jhepr.2024.101216","DOIUrl":"10.1016/j.jhepr.2024.101216","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Current prognostic models for patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE) are not extensively validated and widely accepted. We aimed to develop and validate a continuous model incorporating tumor burden and biology for individual survival prediction and risk stratification.</div></div><div><h3>Methods</h3><div>Overall, 4,377 treatment-naive candidates for whom TACE was recommended, from 39 centers in five countries, were enrolled and divided into training, internal validation, and two external validation datasets. The novel model was developed using a Cox multivariable regression analysis and compared with our original 6-and-12 model (the largest tumor size [ts, centimetres] + tumor number [tn]) and other available models in terms of predictive accuracy.</div></div><div><h3>Results</h3><div>The proposed model, named the ‘6-and-12 model 2.0’, was generated as ‘ts + tn + 1.5×log₁₀ alpha-fetoprotein (AFP)’, showed good discrimination (C-index 0.674) and calibration (Hosmer–Lemeshow test <em>p</em> = 0.147), and outperformed current existing models. An easy-to-use stratification was proposed according to the different AFP levels (≤100, 100–400, 400–2,000, 2,000–10,000, 10,000–40,000, and &gt;40,000 ng/ml) along with the corresponding tumor burden cutoffs (8/14, 7/13, 6/12, 5/11, 4/10, and any tumor burden); that is, if the AFP level was 400–2,000 ng/ml, the stratification should be low-(≤6)/intermediate-(6–12)/high-risk (&gt;12) strata. Hence, it could divide the patients into three distinct risk categories with a median overall survival of 45.0 (95% CI, 40.1–49.9), 30.0 (95% CI, 26.1–33.9), and 15.4 (95% CI, 13.4–17.4) months (<em>p</em> &lt;0.001) from low-risk to high-risk strata, respectively. These findings were confirmed in validation and subgroup analyses.</div></div><div><h3>Conclusions</h3><div>The 6-and-12 model 2.0 significantly improved individual outcome predictions and better stratified the candidates recommended for TACE; thus, this model could be used in both clinical practice and trial design.</div></div><div><h3>Impact and implications:</h3><div>In this international multicentre study, we developed and internally and externally validated a novel outcome prediction model for candidates with HCC who would be ideal for TACE. The model, called the 6-and-12 model 2.0, was based on 4,377 patients from 39 centers in five countries. The model offers individualized outcome prediction, outperforming the original 6-and-12 model score and other existing metrics across all datasets and subsets. Based on different levels of alpha-fetoprotein (AFP) and corresponding cut-offs of tumor burden, patients could be stratified into three risk strata with significantly different survival prognoses, which could provide a referential framework to control study heterogeneity and define the target population in future trial designs.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 1","pages":"Article 101216"},"PeriodicalIF":9.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699734/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acknowledging our reviewers","authors":"","doi":"10.1016/j.jhepr.2024.101244","DOIUrl":"10.1016/j.jhepr.2024.101244","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 1","pages":"Article 101244"},"PeriodicalIF":9.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143160870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatocellular carcinoma hosts cholinergic neural cells and tumoral hepatocytes harboring targetable muscarinic receptors","authors":"Charlotte A. Hernandez ,&nbsp;Claire Verzeroli ,&nbsp;Armando Andres Roca Suarez ,&nbsp;Abud-José Farca-Luna ,&nbsp;Laurie Tonon ,&nbsp;Roger Esteban-Fabró ,&nbsp;Roser Pinyol ,&nbsp;Marie-Laure Plissonnier ,&nbsp;Ievgeniia Chicherova ,&nbsp;Anaëlle Dubois ,&nbsp;Pascale Bellaud ,&nbsp;Marine Seffals ,&nbsp;Bruno Turlin ,&nbsp;Alain Fautrel ,&nbsp;Gabriel Ichim ,&nbsp;Michel Rivoire ,&nbsp;Guillaume Passot ,&nbsp;Zuzana Macek-Jilkova ,&nbsp;Thomas Decaens ,&nbsp;Alain Viari ,&nbsp;Romain Parent","doi":"10.1016/j.jhepr.2024.101245","DOIUrl":"10.1016/j.jhepr.2024.101245","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Owing to unexplained interpatient variation and treatment failure in hepatocellular carcinoma (HCC), novel therapeutic approaches remain an urgent clinical need. Hepatic neurons, belonging to the autonomic nervous system (ANS), mediate liver/whole body crosstalk. Pathological innervation of the ANS has been identified in cancer, nurturing tumor stroma and conferring stronger carcinogenic properties.</div></div><div><h3>Methods</h3><div>We characterized the innervation of liver tumors from the French Liver Biobank, then applied bioinformatics to TCGA (The Cancer Genome Atlas), several other datasets and a European validation cohort, to re-evaluate patient stratification. Cell biology and pharmacology studies were also performed.</div></div><div><h3>Results</h3><div>Densely packed nucleated DCX⁺, synaptophysin⁺, NeuN⁺, VAChT⁺, TH^-, CD31^-, CD45^- clusters, to date undetected, were identified in human HCCs, and independently confirmed by single-cell RNA sequencing data. Using the new concept of a neuronal score, human and rat HCCs displayed tightly netrin-1-associated neural reconfiguration towards cholinergic polarity, which was associated with chronic liver disease progression, cancer onset and many features of aggressive (proliferative class) HCC, including shortened survival. This score was conditioned by tumoral hepatocytes, and predicted sorafenib efficacy in the STORM HCC phase III trial. Conversely, intratumoral adrenergic lymphocytes were enriched in TEMRA and cytotoxic phenotypes. Amongst all cholinergic transcripts, the medically targeted CHRM3 receptor was enriched and associated with pathogenic traits in HCC, as well as poor prognosis in HCC stages 1-2, while its level dropped upon experimental re-differentiation. Its pharmacological inhibition with low concentrations of anticholinergic drugs, but not cholinomimetics, decreased anchorage-independent growth and anoikis, synergized with sorafenib and lenvatinib in HCC class 1 to 3 lines, yet not in primary human hepatocytes, and preserved mature hepatocyte functions.</div></div><div><h3>Conclusion</h3><div>These data identify cholinergic processes as instrumental in liver carcinogenesis and support the use of EMA/FDA-approved cholinergic drugs in HCC research.</div></div><div><h3>Impact and implications:</h3><div>Hepatocellular carcinoma (HCC) care has long been hampered by the enigmatic nature of disease evolution, as well as of response or resistance to treatment. Hepatic neurons are likely the least studied liver cell type and mediate patients singularities from the ANS to the organ in real-time. Cholinergic inputs identified in this study as pathogenic may be targeted with the well charted pharmacopoeia of neurotropic drugs already available, for basic or clinical research purposes, with an expected high level of safety.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 1","pages":"Article 101245"},"PeriodicalIF":9.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11663970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}