Featured
-
-
Article
| Open AccessNeoadjuvant tislelizumab plus stereotactic body radiotherapy and adjuvant tislelizumab in early-stage resectable hepatocellular carcinoma: the Notable-HCC phase 1b trial
The feasibility and efficacy of neoadjuvant immunotherapy for resectable hepatocellular carcinoma (HCC) have been previously suggested. Here the authors report the results of a phase 1b trial of neoadjuvant tislelizumab plus stereotactic body radiotherapy and adjuvant tislelizumab in early-stage resectable HCC.
- Zhongchao Li
- , Jing Liu
- & Lei Zhao
-
Article
| Open AccessTumor phylogeography reveals block-shaped spatial heterogeneity and the mode of evolution in Hepatocellular Carcinoma
Hepatocellular carcinomas (HCC) present spatial intratumour heterogeneity (sITH). Here, the authors perform a genomic and phylogenetic analysis of spatially-sampled HCC tumour sections, observe block-shaped sITH, and find ongoing natural selection where ancestral and derived clones spatially compete in the same tumor.
- Xiaodong Liu
- , Ke Zhang
- & Weiwei Zhai
-
Article
| Open AccessSingle-cell multiomics reveals the interplay of clonal evolution and cellular plasticity in hepatoblastoma
Hepatoblastoma (HB) is the most frequent paediatric liver tumour with heterogeneous cellular phenotypes that influence clinical outcomes. Here, the authors integrate bulk, single-cell, and spatial multi-omics to characterise HB cells, and find that clonal evolution and epigenetic plasticity shape response to therapy.
- Amélie Roehrig
- , Theo Z. Hirsch
- & Eric Letouzé
-
Article
| Open AccessCancer cell genetics shaping of the tumor microenvironment reveals myeloid cell-centric exploitable vulnerabilities in hepatocellular carcinoma
Distinct genetic mutations can shape the tumor immune microenvironment. Here the authors generate preclinical mouse models of hepatocellular carcinoma bearing clinically-relevant oncogenic driver combinations, identifying myeloid cell-centric exploitable therapeutic vulnerabilities.
- Christel F. A. Ramirez
- , Daniel Taranto
- & Leila Akkari
-
Article
| Open AccessThe phosphatidylserine targeting antibody bavituximab plus pembrolizumab in unresectable hepatocellular carcinoma: a phase 2 trial
Bavituximab is a genetically engineered IgG1 chimeric antibody that targets phosphatidylserine. Here the authors report the results of a single-arm phase 2 trial of bavituximab in combination with pembrolizumab (anti-PD1) for patients with unresectable hepatocellular carcinoma.
- David Hsiehchen
- , Muhammad S. Beg
- & Adam C. Yopp
-
Article
| Open AccessThe transcription factor ChREBP Orchestrates liver carcinogenesis by coordinating the PI3K/AKT signaling and cancer metabolism
Cancer cells adapt to changes in metabolism to ensure their survival. Here the authors show that glucose responsive transcription factor ChREBP reprograms liver cancer metabolism in part via enhancing the PI3K/AKT signaling.
- Emmanuel Benichou
- , Bolaji Seffou
- & Renaud Dentin
-
Article
| Open AccessSerum amyloid A promotes glycolysis of neutrophils during PD-1 blockade resistance in hepatocellular carcinoma
The reasons for why hepatocellular carcinoma (HCC) is unresponsive to anti-PD-1 inhibition in some patients is not fully understood. Here the authors use human samples and mice tumour models to implicate serum amyloid A and STAT3 signalling involvement in the resistance to anti-PD1 immunotherapy in HCC.
- Meng He
- , Yongxiang Liu
- & Ning Lyu
-
Article
| Open AccessHKDC1 promotes tumor immune evasion in hepatocellular carcinoma by coupling cytoskeleton to STAT1 activation and PD-L1 expression
Aberrant expression of the human hexokinase HKDC1 has been observed in patients with cancer. Here the authors report that HKDC1 expression is associated with hepatocellular carcinoma progression and PD-L1 mediated immune evasion.
- Yi Zhang
- , Mingjie Wang
- & Ping Gao
-
Article
| Open AccessA multicenter clinical AI system study for detection and diagnosis of focal liver lesions
Early detection and accurate diagnosis of focal liver lesions are crucial for effective treatment and prognosis. Here, the authors present a fully automated diagnostic system that leverages multi-phase CT scans and clinical features, for diagnosing liver lesions.
- Hanning Ying
- , Xiaoqing Liu
- & Xiujun Cai
-
Article
| Open AccessTargeting ALK averts ribonuclease 1-induced immunosuppression and enhances antitumor immunity in hepatocellular carcinoma
Immune checkpoint inhibitors have now been approved for the treatment of advanced hepatocellular carcinoma (HCC), however only a minority of patients appear to benefit. Here the authors report that RNase1 levels predict response to nivolumab (anti-PD1) in patients with HCC and that RNase 1 overexpression correlates with an immunosuppressive tumor microenvironment in HCC preclinical models.
- Chunxiao Liu
- , Chenhao Zhou
- & Mien-Chie Hung
-
Article
| Open AccessTET2-mediated tumor cGAS triggers endothelial STING activation to regulate vasculature remodeling and anti-tumor immunity in liver cancer
Activation of the cGAS-STING pathway has been associated with the promotion of anti-tumor immunity. Here the authors show that TET2 upregulates tumor cGAS to activate STING in endothelial cells, inducing tumor vascular normalization and enhancing efficacy of anti-PD-L1 alone or combined with IL-2 in liver cancer preclinical models.
- Hongwei Lv
- , Qianni Zong
- & Wen Yang
-
Article
| Open AccessProteomics-driven noninvasive screening of circulating serum protein panels for the early diagnosis of hepatocellular carcinoma
Hepatocellular carcinoma is often diagnosed at a late stage which limits treatment efficacy. Here, the authors utilise proteomics to identify serum proteomic biomarkers for early diagnosis, and validate using a prospective validation cohort.
- Xiaohua Xing
- , Linsheng Cai
- & Xiaolong Liu
-
Article
| Open AccessDeep learning-based phenotyping reclassifies combined hepatocellular-cholangiocarcinoma
Combined hepatocellular-cholangiocarcinomas (cHCC-CCA) are challenging to diagnose, as they exhibit features of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICCA). Here, the authors use deep learning to re-classify cHCC-CCA tumours into HCC or ICCA based on histopathology images.
- Julien Calderaro
- , Narmin Ghaffari Laleh
- & Jakob Nikolas Kather
-
Article
| Open AccessSPINK1-induced tumor plasticity provides a therapeutic window for chemotherapy in hepatocellular carcinoma
In liver cancer, the presence of tumour-initiating cell subsets are associated with poorer prognosis and chemotherapy resistance in liver cancer. Here, the authors show that upon treatment with 5-FU or cisplatin, this subset releases SPINK1 which binds EGFR, activating the ERK-CDK4/6-E2F2 signaling cascade and resulting in chemoresistance.
- Ki-Fong Man
- , Lei Zhou
- & Stephanie Ma
-
Article
| Open AccessPD-1- CD45RA+ effector-memory CD8 T cells and CXCL10+ macrophages are associated with response to atezolizumab plus bevacizumab in advanced hepatocellular carcinoma
Although atezolizumab and bevacizumab have changed the treatment landscape of advanced hepatocellular carcinoma, the factors that determine responsiveness to treatment remain unclear. Using single-cell RNA sequencing, the authors identify specific macrophage and T cell subsets that are enriched in patients with durable responses.
- Sarah Cappuyns
- , Gino Philips
- & Jeroen Dekervel
-
Article
| Open AccessLow-dose radiotherapy combined with dual PD-L1 and VEGFA blockade elicits antitumor response in hepatocellular carcinoma mediated by activated intratumoral CD8+ exhausted-like T cells
An increasing number of preclinical and clinical studies have investigated the antitumor efficacy of combined radiotherapy and immunotherapy. Here the authors report that low-dose radiotherapy enhances the antitumor effect of dual VEGFA and PD-L1 blockade in preclinical models of hepatocellular carcinoma.
- Siqi Li
- , Kun Li
- & Yang Yang
-
Article
| Open AccessPreneoplastic liver colonization by 11p15.5 altered mosaic cells in young children with hepatoblastoma
Paediatric liver cancer is rare, and often associated with a predisposition syndrome. Here, the authors show that 11p15.5 mosaic alteration in the liver is a pre-neoplastic lesion associated with hepatoblastoma, and spatial transcriptomics together with single-nucleus RNAseq identify a an altered zonation in the liver of these patients.
- Jill Pilet
- , Theo Z. Hirsch
- & Jessica Zucman-Rossi
-
Article
| Open AccessCathepsin-facilitated invasion of BMI1-high hepatocellular carcinoma cells drives bile duct tumor thrombi formation
Bile duct tumor thrombosis (BDTT) is a complication associated with advanced hepatocellular carcinoma (HCC) which can severely limits quality of life. Here, the authors develop a spontaneous BDTT mouse model to investigate the cellular original and mechanism underlying the formation of BDTT.
- Lei-Bo Xu
- , Yu-Fei Qin
- & Ping-Pui Wong
-
Article
| Open AccessURI alleviates tyrosine kinase inhibitors-induced ferroptosis by reprogramming lipid metabolism in p53 wild-type liver cancers
Despite being a promising treatment for hepatocellular carcinoma (HCC), resistance to tyrosine kinase inhibitors (TKI) present a major obstacle. Here, the authors demonstrate that lipid metabolism reprogramming via URI mediated stearoyl-CoA desaturase 1 upregulation present a targetable driver of sorafenib resistance in HCC.
- Zhiwen Ding
- , Yufei Pan
- & Lu Wang
-
Article
| Open AccessGenome-wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high-risk hepatoblastoma
The availability of relevant animal models that can recapitulate high-risk hepatoblastoma will help to better understand its pathogenesis. Here the authors report and characterize a hepatocyte-specific, MYC-driven hepatoblastoma mouse model and show it recapitulates the human hepatoblastoma pathophysiology.
- Jie Fang
- , Shivendra Singh
- & Jun Yang
-
Article
| Open AccessAlternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes
The regulatory mechanisms of alternative promoters remain to be investigated. Here, the authors explore the sequence and epigenetics landscape of alternative promoters and how they regulate gene expression in hepatocellular carcinoma.
- Chirag Nepal
- & Jesper B. Andersen
-
Article
| Open AccessHepatic stellate cell stearoyl co-A desaturase activates leukotriene B4 receptor 2 - β-catenin cascade to promote liver tumorigenesis
Activated hepatic stellate cells (aHSC) promote hepatocellular carcinoma (HCC). Here the authors show that selective ablation of stearoyl CoA desaturase-2 in aHSC suppresses leukotriene B4 receptor 2-dependent nuclear β-catenin signaling, preventing liver tumorigenesis.
- Sonal Sinha
- , Satoka Aizawa
- & Hidekazu Tsukamoto
-
Article
| Open AccessPHGDH arginine methylation by PRMT1 promotes serine synthesis and represents a therapeutic vulnerability in hepatocellular carcinoma
The role of protein arginine methylation in serine metabolism of cancer cells in hepatocellular carcinoma (HCC) remains to be explored. Here, the authors show that phosphoglycerate dehydrogenase (PHGDH) is activated by PRMT1-mediated R236 methylation, promoting serine synthesis, redox homeostasis and HCC growth.
- Kui Wang
- , Li Luo
- & Canhua Huang
-
Article
| Open AccessRapid, label-free histopathological diagnosis of liver cancer based on Raman spectroscopy and deep learning
Biopsy is recommended for definitive diagnosis of liver carcinoma, however, this process requires staining and expert pathologists to confirm diagnosis. Here, the authors employ a portable Raman spectroscopy system combined with deep learning to detect carcinoma from normal tissue in real time.
- Liping Huang
- , Hongwei Sun
- & Yi Wang
-
Article
| Open AccessMultiregional single-cell dissection of tumor and immune cells reveals stable lock-and-key features in liver cancer
Multiregion sequencing is needed to better capture the heterogeneity of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Here, the authors analyse HCC and iCCA tumours with multiregion single-cell RNA-seq, revealing cellular dynamics and communication networks with immune cells.
- Lichun Ma
- , Sophia Heinrich
- & Xin Wei Wang
-
Article
| Open AccessGenetic features and therapeutic relevance of emergent circulating tumor DNA alterations in refractory non-colorectal gastrointestinal cancers
Acquired resistance can be associated with genetic changes, however, clinical molecular profiling is usually only considered at the time of diagnosis. Here, the authors use serial ctDNA profiling of 449 gastrointestinal cancers to demonstrate widespread tumour evolution associated with treatment resistance and its potential implications for treatment.
- David Hsiehchen
- , Leslie Bucheit
- & Hao Zhu
-
Article
| Open AccessProteo-genomic characterization of virus-associated liver cancers reveals potential subtypes and therapeutic targets
The molecular heterogeneity of primary liver cancer remains to be characterised. Here, the authors perform multi-omics analysis of 259 primary liver cancer tissues and identify three distinct molecular subtypes.
- Masashi Fujita
- , Mei-Ju May Chen
- & Hidewaki Nakagawa
-
Article
| Open AccessThe oncogenic fusion protein DNAJB1-PRKACA can be specifically targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma
The DNAJB1-PRKACA fusion transcript is the oncogenic driver in fibrolamellar hepatocellular carcinoma, a lethal disease with limited therapeutic options. Here, the authors identify the DNAJB1-PRKACA protein as a source for immunogenic neoepitopes and a potential target of T cell-based immunotherapy.
- Jens Bauer
- , Natalie Köhler
- & Juliane S. Walz
-
Article
| Open AccessA single-cell atlas of the multicellular ecosystem of primary and metastatic hepatocellular carcinoma
The immune cell constituents and localisation within human hepatocellular carcinoma is not fully understood. Here the authors use single cell RNA sequencing of HCC from four different tissue sites and show differences between primary and metastatic tumours, tumour associated macrophages and immune cell populations.
- Yiming Lu
- , Aiqing Yang
- & Gangqiao Zhou
-
Article
| Open AccessImbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment
Steatohepatitis is a chronic hepatic inflammation associated with increased risk of hepatocellular carcinoma progression. Here the authors show that intestinal dysbiosis in mice lacking the inflammasome sensor molecule NLRP6 aggravates steatohepatitis and accelerates liver cancer progression, a process that can be delayed by antibiotic treatment.
- Kai Markus Schneider
- , Antje Mohs
- & Christian Trautwein
-
Article
| Open AccessFUNDC2 promotes liver tumorigenesis by inhibiting MFN1-mediated mitochondrial fusion
Fragmented mitochondria are a frequent hallmark of cancer, but the cause and consequence are less clear. The authors demonstrate that elevated FUNDC2 causes mitochondrial fragmentation through inhibition of MFN1 in hepatocellular carcinoma and that knockdown of FUNDC2 inhibits liver tumorigenesis in mice.
- Shuaifeng Li
- , Shixun Han
- & Bin Zhao
-
Article
| Open AccessIntegrative proteogenomic characterization of hepatocellular carcinoma across etiologies and stages
Proteogenomic analyses of hepatocellular carcinomas (HCC) have focused on early-stage, HBV-associated tumours and lacked information about the phosphoproteome. Here, the authors present a comprehensive HCC proteogenomics and phosphoproteomics study in patient samples from multiple etiologies and stages.
- Charlotte K. Y. Ng
- , Eva Dazert
- & Markus H. Heim
-
Article
| Open AccessTrajectory of immune evasion and cancer progression in hepatocellular carcinoma
In order to design cancer immune therapies, it is important to understand how tumours evade the immune response that is mounted against them. Authors here analyse the distribution and properties of immune cells in hepatocellular carcinoma and describe a progressive tumour-immune co-evolution programme from early to late stage cancer.
- Phuong H. D. Nguyen
- , Martin Wasser
- & Valerie Chew
-
Article
| Open AccessCharacterisation and induction of tissue-resident gamma delta T-cells to target hepatocellular carcinoma
Many cancer immune therapy approaches depend on an HLA-restricted neoantigen-specific T cell response. AUs show here that Zoledronic acid can expand, and induce tumour recognition by, a population of tissue resident memory gamma-delta T cells associated with an efficient anti-tumour immune response in hepatocellular carcinoma.
- Nekisa Zakeri
- , Andrew Hall
- & Mala K. Maini
-
Article
| Open AccessThe aberrant upregulation of exon 10-inclusive SREK1 through SRSF10 acts as an oncogenic driver in human hepatocellular carcinoma
Alternative splicing is dysregulated in hepatocellular carcinoma. Here, the authors investigate the role of the splice variant of Splicing Regulatory Glutamic Acid and Lysine Rich Protein 1 (SREK1) and its upstream regulator, Serine/arginine-rich splicing factor 10 (SRSF10) in sustaining the oncogenic signal.
- Cunjie Chang
- , Muthukumar Rajasekaran
- & Jianxiang Chen
-
Article
| Open AccessAn enhancer variant at 16q22.1 predisposes to hepatocellular carcinoma via regulating PRMT7 expression
The role of enhancer variants in hepatocellular carcinoma (HCC) predisposition remains unknown. Here, the authors perform a genome-wide survey of HCC-susceptible enhancer variants in 11,958 individuals, identify rs73613962 within the intronic region of PRMT7 and find that PRMT7 upregulation predisposes to HCC.
- Ting Shen
- , Ting Ni
- & De-Ke Jiang
-
Article
| Open AccessHypoxia-induced macropinocytosis represents a metabolic route for liver cancer
Cancer cells rely on macropinocytosis to scavenge extracellular proteins for growth. Here the authors show that macropinocytosis supports the survival of hypoxic hepatocellular carcinoma cells and this is dependent on HIF-1, which in turns activates the transcription of a membrane ruffling protein, EH domain-containing protein 2.
- Misty Shuo Zhang
- , Jane Di Cui
- & Carmen Chak-Lui Wong
-
Article
| Open AccessRNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state
The E3 ubiquitin ligases RNF43/ZNRF3 are often mutated in cancer but their precise contribution to liver disease is unknown. Here, the authors show that RNF43/ZNRF3 alterations predispose to liver cancer by controlling the differentiation and lipid metabolic state of hepatocytes.
- Germán Belenguer
- , Gianmarco Mastrogiovanni
- & Meritxell Huch
-
Article
| Open AccessA targetable LIFR−NF-κB−LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis
Leukemia inhibitory factor receptor (LIFR) is frequently downregulated in liver cancer. Here the authors show that loss of LIFR promotes liver tumorigenesis and confers resistance to drug-induced ferroptosis through NF-κB-mediated upregulation of iron-sequestering cytokine LCN2.
- Fan Yao
- , Yalan Deng
- & Li Ma
-
Article
| Open AccessGrowth differentiation factor 1-induced tumour plasticity provides a therapeutic window for immunotherapy in hepatocellular carcinoma
Poorly differentiated hepatocellular carcinoma (HCC) is an aggressive disease with poor prognosis. Here the authors show that GDF1, a member of the TGF-β superfamily, is highly expressed in high-grade poorly differentiated HCC and is associated with tumor plasticity, and that GDF1-induced reexpression of cancer testis antigens could render tumors sensitive to immune checkpoint inhibition.
- Wei Cheng
- , Hao-Long Li
- & Ming Liu
-
Article
| Open AccessAberrant integration of Hepatitis B virus DNA promotes major restructuring of human hepatocellular carcinoma genome architecture
Hepatitis B virus (HBV) infection and DNA integration is a frequent cause of hepatocellular carcinoma (HCC), but the consequences of this process are not fully understood. Here the authors use whole-genome and long-read sequencing data from HCC patient samples to study the timing and alterations induced by HBV insertions.
- Eva G. Álvarez
- , Jonas Demeulemeester
- & Jose M. C. Tubio
-
Article
| Open AccessHigher intake of whole grains and dietary fiber are associated with lower risk of liver cancer and chronic liver disease mortality
Higher intake of dietary fiber and whole grains are associated with reduced risk of various diseases including some cancers. Here, the authors estimate reductions in liver cancer of 22% and 31% and chronic liver disease mortality of 56% and 63% associated with increased whole grain and dietary fiber intake, respectively.
- Xing Liu
- , Wanshui Yang
- & Xuehong Zhang
-
Article
| Open AccessN1-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism
Metabolic adaptation has been reported to promote cancer, yet the underlying mechanisms are not clear. Here, the authors show that m1A methylation in tRNA regulates cholesterol metabolism in liver cancer stem cells and m1A inhibition decreases tumourigenesis in preclinical models of hepatocellular carcinoma.
- Yanying Wang
- , Jing Wang
- & Zusen Fan
-
Article
| Open AccessIntracellular delivery of protein drugs with an autonomously lysing bacterial system reduces tumor growth and metastases
The limited ability of cancer therapeutics in crossing the cancer cell membrane hampers their therapeutic potential. Here, the authors report Salmonella-based system for intracellular delivery of protein drugs, e.g. caspase-3, and show reduction of tumors in mouse models of breast and liver cancer.
- Vishnu Raman
- , Nele Van Dessel
- & Neil S. Forbes
-
Article
| Open AccessEnvironmental eustress modulates β-ARs/CCL2 axis to induce anti-tumor immunity and sensitize immunotherapy against liver cancer in mice
The impact of positive environment stimulations (eustress) on cancer biology remains poorly understood. Here the authors show that exposure to an environment enrichment stimulates anti-tumor immunity and reduces tumor growth in preclinical models of liver cancer.
- Chaobao Liu
- , Yang Yang
- & Hui Wang
-
Article
| Open AccessA human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery
Drug and target discovery for advanced liver disease are hampered by a lack of suitable models for clinical translation. Here the authors present a human liver cell-based system modeling a clinical prognostic signature allowing to propose nizatidine for treatment of advanced liver fibrosis and hepatocellular carcinoma prevention.
- Emilie Crouchet
- , Simonetta Bandiera
- & Thomas F. Baumert
-
Article
| Open AccessDissecting spatial heterogeneity and the immune-evasion mechanism of CTCs by single-cell RNA-seq in hepatocellular carcinoma
Circulating tumour cells can be useful for monitoring disease progression but how they survive in the circulatory system is unclear. Here, the authors use single-cell sequencing of circulating tumour cells from multiple vascular sites in liver cancer patients and identify genes that may help the cells survive.
- Yun-Fan Sun
- , Liang Wu
- & Xin-Rong Yang
-
Article
| Open AccessSingle-cell RNA sequencing shows the immunosuppressive landscape and tumor heterogeneity of HBV-associated hepatocellular carcinoma
Different cells of the tumour microenvironment in HBV-associated human hepatocellular carcinoma (HCC) interact to promote tumour immunity. Here the authors use single cell RNA sequencing to identify TIGIT-NECTIN2 as a pathway by which tumour-associated macrophages reduce intratumour T cell activation.
- Daniel Wai-Hung Ho
- , Yu-Man Tsui
- & Irene Oi-Lin Ng
-
Article
| Open AccessWSX1 act as a tumor suppressor in hepatocellular carcinoma by downregulating neoplastic PD-L1 expression
The biological functions of WSX1, the alpha subunit of the interleukin-27 receptor, in non-immune cells are largely unknown. Here, the authors propose an IL-27-independent tumor suppressor role for WSX1 in hepatocytes, showing that WSX1 restricts tumor progression by down-regulating PD-L1 expression in tumour cells and maximizing T cell mediated antitumor immune responses.
- Man Wu
- , Xueqing Xia
- & Shulin Li