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Liver Cancer Awareness Month

Globally, liver cancer is the second leading cause of cancer-related deaths. It is mainly associated with liver cirrhosis, hepatitis B or C virus infection, or nonalcoholic steatohepatitis. Unfortunately, liver cancer can be difficult to treat as the disease is often advanced at the time of diagnosis. Generally, liver surgery and ablation therapies are the most common approaches used in the treatment of both primary and metastatic liver tumours. There are also a number of treatments aimed at reducing the growth of the cancer if surgery is not an option, including chemotherapy, targeted radiotherapy and targeted therapies.

October is Liver Cancer Awareness month and the cancer team at Nature Communications is pleased to share important research articles in this field to raise awareness and increase understanding of this challenging disease and find effective ways to treat it.

Featured articles

While hepatoblastoma is the most common pediatric liver cancer, its molecular background has not been fully characterised. Here, the authors perform genomic and epigenomic profiling of 163 untreated pediatric liver tumours and suggest the upregulation of ASCL2 and methylation patterns of IGF2 promoters in driving hepatoblast carcinogenesis.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

Restoring oxygenation in hypoxic tumors might lead to favorable oncological outcome of patients if combined with standard multimodal therapy regimens. Here the authors report a phase Ib clinical trial of anti-hypoxic myo-inositol trispyrophosphate (ITPP) in hepato-pancreato-biliary neoplasms.

Article | Open Access | | Nature Communications

Glycogen Storage Disease 1a (Gsd1a) is an inherited disorder caused by glucose 6-phosphatase (G6Pase-α) deficiency and characterized by hypoglycaemia and high risk of liver cancer. Here the authors develop a mRNA-based G6Pase-α delivery therapy that is efficacious and safe in a mouse model of GSD1a.

Article | Open Access | | Nature Communications

Shared metabolic pathways could allow simultaneous manipulation of T cells, viruses and tumours. Here the authors show targeting cholesterol esterification restrains hepatitis B in vitro, whilst bolstering exhausted antigen-specific T cell responses from human liver and hepatocellular carcinoma.

Article | Open Access | | Nature Communications

Liver cancer typically arises after years of inflammatory insults to hepatocytes. These cells can change their ploidy state during health and disease. Whilst polyploidy may offer some protection, new research shows it may also promote the formation of liver tumours.

Comment | Open Access | | Nature Communications

Cancer cell clusters metastasize to distant organ by polyclonal manner. Here, the authors show that malignant subclone induces fibrotic niche generation in the liver by hepatic stellate cell activation, supporting survival and colonization of non-metastatic cells to develop polyclonal metastasis.

Article | Open Access | | Nature Communications

Intratumoural heterogeneity is a feature of liver cancer. Here, the authors demonstrate that heterogeneity exists at the immune cell level in liver cancer and show that tumours with high intratumoural immune heterogeneity demonstrated an immune suppressive microenvironment, which was associated with tumour evolution and a poor prognosis.

Article | Open Access | | Nature Communications

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease characterized by an immunosuppressive microenvironment. Here the authors show that a subset of P2RX1-negative neutrophils with immunosuppressive properties accumulate in PDAC metastatic liver tissues and promote tumor growth.

Article | Open Access | | Nature Communications

Aquaporin 3 (AQP3) is a transporter of water, glycerol and hydrogen peroxide, and hydrogen peroxide mediated oxidative stress has been implicated in liver injury. Here, the authors report the development of an anti-AQP3 monoclonal antibody, which alleviates liver injury in multiple mouse models.

Article | Open Access | | Nature Communications

More featured articles

The molecular determinants of differential responses of different cancer cells to methionine restriction are poorly understood. Here the authors show that hepatocyte nuclear factor 4α regulates sulfur amino acid metabolism and dictates the sensitivity of liver cancer to this dietary manipulation.

Article | Open Access | | Nature Communications

Non-alcoholic fatty liver (NAFLD) disease causes degeneration of the liver, affects about 25% of people globally, and has no approved treatment. Here, the authors show that the therapeutic siRNA-driven silencing of MCJ in the liver is an effective and safe treatment for NAFLD in multiple mouse models.

Article | Open Access | | Nature Communications

Extracellular vesicles (EVs) are present in circulation at relatively early stages of disease, providing potential opportunities for early cancer diagnosis. Here, the authors report a covalent chemistry-based hepatocellular carcinoma (HCC)-specific EV purification system for early detection of HCC by performing digital scoring on the purified EVs.

Article | Open Access | | Nature Communications

Mongolia has the highest incidence of—and mortality from—hepatocellular carcinoma (HCC) in the world. Here, the authors examine the genomic and transcriptomic landscape of Mongolian HCC, uncover novel driver mutations, and suggest distinct disease etiologies.

Article | Open Access | | Nature Communications

Informative pathways driving cancer pathogenesis and subtypes can be difficult to identify in the presence of many gene interactions irrelevant to cancer. Here, the authors describe an approach for cancer gene pathway analysis based on key molecular interactions that drive cancer in relevant tissue types, and they assemble a focused map of Evolutionarily Selected Pathways (ESP) with interactions supported by both protein–protein binding and genetic epistasis during somatic tumor evolution.

Article | Open Access | | Nature Communications

It is known that estrogens can affect the immune response to cancer. Here, the authors show that estrogen depletion through ovariectomy reduces the extent of liver metastasis and that this is accompanied by a decrease in the number and function of immunosuppressive cells in the metastatic microenvironment.

Article | Open Access | | Nature Communications

Non alcoholic fatty liver disease (NAFLD) associates with an elevated risk of developing hepatocellular carcinoma (HCC). Here, the authors find that Nogo-B, an endoplasmic reticulum resident protein, is upregulated by lipid uptake and acts as an oncogene in NAFLD-associated HCC by promoting lipid droplet breakdown by lipophagy and triggering Hippo pathway dysregulation

Article | Open Access | | Nature Communications

Colorectal cancers (CRCs) often develop into untreatable metastatic disease of the liver. Here the authors report the modification of extracellular matrix proteins by citrullination in CRC metastases to the liver and propose that inhibition of citrullination could serve as therapeutic avenue in the treatment.

Article | Open Access | | Nature Communications

Hippo-YAP pathway plays an important role in cancers; however the in vivo relevance of YAP/TAZ target genes is unclear. Here, the authors show that NUAK2 is a target of YAP and participates in a feedback loop to maximize YAP activity. Inhibition of NUAK2 suppresses YAP-driven hepatomegaly and liver cancer growth, offering a new target for cancer therapy.

Article | Open Access | | Nature Communications

How tumor cells control metastatic niche formation is not fully understood. Here, the authors show in a lung metastatic niche, high-metastatic hepatocellular carcinoma cells secrete exosomal miR-1247-3p that leads to activation of β1-integrin-NF-κBsignalling, converting fibroblasts to cancer-associated fibroblasts.

Article | Open Access | | Nature Communications

Hepatocyte nuclear factor 4 alpha (HNF4α) is regulated by different promoters to generate two isoforms, one of which functions as a tumor suppressor. Here, the authors reveal that induction of the alternative isoform in hepatocellular carcinoma inhibits the circadian clock by repressing BMAL1, and the reintroduction of BMAL1 prevents HCC tumor growth.

Article | Open Access | | Nature Communications

More featured articles

The oligometastasis hypothesis suggests certain metastases are limited in extent and curable with focal therapies. Here they identify three integrated molecular subtypes of colorectal cancer liver metastasis, which complement clinical risk stratification to distinguish the subset of oligometastatic patients.

Article | Open Access | | Nature Communications

Nonalcoholic steatohepatitis (NASH) and dietary cholesterol are risk factors for hepatocellular carcinoma (HCC). Here, the authors utilise mouse models to show that dietary cholesterol induces NASH by deregulating genes involved in metabolism, inflammation and calcium signaling to induce NASH-HCC.

Article | Open Access | | Nature Communications

Increased levels of the Yap oncoprotein stimulate liver growth and promote hepatocarcinogenesis. Here the authors show that hepatocyte-specific loss of Atg7 in mice leads to decreased autophagic degradation of Yap and liver overgrowth, and further establish this association in human liver cancer tissues.

Article | Open Access | | Nature Communications

Changes in the DNA methylation status are commonly observed in cancer but their impact on cancer development is unclear. Here, combining DNA methylation and expression profiles from a murine model of hepatocellular carcinoma with those from human samples, the authors report an epigenetic reprogramming process ensuring increased dosage of an “oncogene module”.

Article | Open Access | | Nature Communications

Tumorigenesis is a complex process driven by numerous risk factors. Here, genomic analysis of liver cancer reveals the evolution of mutational signatures during tumor development, highlighting mutational and structural signatures linked to environmental exposures and endogenous cellular processes.

Article | Open Access | | Nature Communications

The lipogenic pathway is often upregulated in liver tumours and regarded as a therapeutic target. Here, the authors show instead that blocking lipogenesis via knockout of acetyl-CoA carboxylase genes results in increased susceptibility to liver tumorigenesis associated with an increased antioxidant defence.

Article | Open Access | | Nature Communications

Fibroblast Growth Factor 19 (FGF19) neutralizing antibodies inhibit hepatocellular carcinoma (HCC) growth but have safety issues. Here, the authors show that FGF19 promotes HCC by activating STAT3 signalling via IL-6 production and that targeting IL-6 pathway abolishes FGF19-induced HCC without side effects.

Article | Open Access | | Nature Communications

Gluconeogenesis is downregulated in hepatocellular carcinoma. Here, the authors show that nuclear receptor Nur77 acts as a tumour suppressor sustaining gluconeogenesis by enhancing phosphoenolpyruvate carboxykinase (PEPCK1) stability via regulating its interaction with the SUMO-conjugating enzyme Ubc9.

Article | Open Access | | Nature Communications