Lymphotoxin beta-activated LTBR/NIK/RELB axis drives proliferation in cholangiocarcinoma.

Background And Aims: Cholangiocarcinoma (CCA) is an aggressive malignancy arising from the intrahepatic (iCCA) or extrahepatic (eCCA) bile ducts with poor prognosis and limited treatment options. Prior evidence highlighted a significant contribution of the non-canonical NF-κB signalling pathway in initiation and aggressiveness of different tumour types. Lymphotoxin-β (LTβ) stimulates the NF-κB-inducing kinase (NIK), resulting in the activation of the transcription factor RelB.

A 5:2 intermittent fasting regimen ameliorates NASH and fibrosis and blunts HCC development via hepatic PPARα and PCK1.

The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) and its transition to hepatocellular carcinoma (HCC) are unknown. Here, we identified that an IF 5:2 regimen prevents NASH development as well as ameliorates established NASH and fibrosis without affecting total calorie intake. Furthermore, the IF 5:2 regimen blunted NASH-HCC transition when applied therapeutically.

Intestinal B cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling.

Background & Aims: The progression of non-alcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC.

Lack of Cyclin E1 in hepatocytes aggravates ethanol-induced liver injury and hepatic steatosis in experimental murine model of acute and chronic alcohol-associated liver disease.

Background: Cyclin E1 is the regulatory subunit of cyclin-dependent kinase 2 (Cdk2) and one of the central players in cell cycle progression. We recently showed its crucial role for initiation of liver fibrosis and hepatocarcinogenesis. In the present study, we investigated the role of Cyclin E1 in the development of alcohol-associated liver disease (ALD).

A researcher's guide to preclinical mouse NASH models.

Non-alcoholic fatty liver disease (NAFLD) and its inflammatory form, non-alcoholic steatohepatitis (NASH), have quickly risen to become the most prevalent chronic liver disease in the Western world and are risk factors for the development of hepatocellular carcinoma (HCC). HCC is not only one of the most common cancers but is also highly lethal. Nevertheless, there are currently no clinically approved drugs for NAFLD, and NASH-induced HCC poses a unique metabolic microenvironment that may influence responsiveness to certain treatments.

Nrf2 induces malignant transformation of hepatic progenitor cells by inducing β-catenin expression.

The Nrf2 signaling pathway prevents cancer initiation, but genetic mutations that activate this pathway are found in various types of cancer. The molecular mechanisms underlying this Janus-headed character are still not understood. Here, we show that sustained Nrf2 activation induces proliferation and dedifferentiation of a Wnt-responsive perivenular hepatic progenitor cell population, transforming them into metastatic cancer cells.

NASH and Hepatocellular Carcinoma: Immunology and Immunotherapy.

The last 10 years have revolutionized our basic understanding of nonalcoholic fatty liver disease and consequent liver cancer. It has become clear that several innate and adaptive immune cells play an important role in initiating, maintaining, or exacerbating nonalcoholic steatohepatitis (NASH)-a disease that has been recently defined as autoaggressive. Despite improved disease management aimed at reducing the progression of fibrosis, NASH is set to become a leading cause for hepatocellular carcinoma (HCC).

T cells: Friends and foes in NASH pathogenesis and hepatocarcinogenesis.

In association with the pandemic spreading of obesity and metabolic syndrome, the prevalence of NAFLD-related HCC is increasing almost exponentially. In recent years, many of the underlining multifactorial causes of NAFLD have been identified, and the cellular mechanisms sustaining disease development have been dissected up to the single-cell level. However, there is still an urgent need to provide clinicians with more therapeutic targets, with particular attention on NAFLD-induced HCC, where immune checkpoint inhibitors do not work as efficiently.

Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer.

Metabolic reprogramming and epigenetic changes have been characterized as hallmarks of liver cancer. Independently of etiology, oncogenic pathways as well as the availability of different energetic substrates critically influence cellular metabolism, and the resulting perturbations often cause aberrant epigenetic alterations, not only in cancer cells but also in the hepatic tumor microenvironment. Metabolic intermediates serve as crucial substrates for various epigenetic modulations, from post-translational modification of histones to DNA methylation.

The immunological and metabolic landscape in primary and metastatic liver cancer.

The liver is the sixth most common site of primary cancer in humans, and generally arises in a background of cirrhosis and inflammation. Moreover, the liver is frequently colonized by metastases from cancers of other organs (particularly the colon) because of its anatomical location and organization, as well as its unique metabolic and immunosuppressive environment. In this Review, we discuss how the hepatic microenvironment adapts to pathologies characterized by chronic inflammation and metabolic alterations.

XCR1 type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are prevalent liver conditions that underlie the development of life-threatening cirrhosis, liver failure and liver cancer. Chronic necro-inflammation is a critical factor in development of NASH, yet the cellular and molecular mechanisms of immune dysregulation in this disease are poorly understood. Here, using single-cell transcriptomic analysis, we comprehensively profiled the immune composition of the mouse liver during NASH.

Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis.

Background And Aims: Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is increasing globally, but its molecular features are not well defined. We aimed to identify unique molecular traits characterising NASH-HCC compared to other HCC aetiologies.

Methods: We collected 80 NASH-HCC and 125 NASH samples from 5 institutions.

Auto-aggressive CXCR6 CD8 T cells cause liver immune pathology in NASH.

Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer. The accumulation of metabolites leads to cell stress and inflammation in the liver, but mechanistic understandings of liver damage in NASH are incomplete. Here, using a preclinical mouse model that displays key features of human NASH (hereafter, NASH mice), we found an indispensable role for T cells in liver immunopathology.

Solving problems is smart, preventing them is wise: Lessons learned from the 2nd International DKFZ Conference on Cancer Prevention.

The 2nd International DKFZ Conference on Cancer Prevention (CCP2020) organized by the German Cancer Research Center (DKFZ) was held as a virtual event on 17-18 September 2020. The event gathered experts on cancer prevention from around the world with the aim of generating a stimulating interchange of opinions between clinicians and basic researchers working in the field. The talks and posters of the conference fueled exciting discussions and debates about the state of the art of cancer prevention and provided a comprehensive outlook on the many aspects of the field.

PKCλ/ι Loss Induces Metabolic Reprogramming in Liver Cancer: Hitting Two Birds with One Stone?

In this issue of Cancer Cell, Kudo et al. identify a novel tumor suppressor role for PKCλ/ι in hepatocellular carcinoma. Loss of PKCλ/ι in obesity-driven liver cancer results in cellular metabolic reprogramming that induces two reciprocally sustainable processes, oxidative phosphorylation and autophagy, which promote liver-tumor aggressiveness in an NRF2-dependent manner.

Guidelines and Considerations for Metabolic Tolerance Tests in Mice.

The epidemic of the century, Diabetes Mellitus (DM) is continuously rising. Intensive research is urgently needed whereby experimental models represent an essential tool to optimise the diagnostic strategy and to improve therapy. In this review, we describe the central principles of the metabolic tests available in order to study glucose and insulin homeostasis in mice, focusing on the most widely used - the glucose and insulin tolerance tests.

Platelets in chronic liver disease, from bench to bedside.

In the last decade, numerous studies revealed physiologic and pathophysiologic roles of platelets beyond haemostasis, a process to prevent and stop bleeding. These include the activation of the immune system and the promotion of inflammation, infection and cancer. Hence, the emerging view on the role of platelets has shifted - platelets are now seen as alert "sentinels" of the immune compartment, rather than passive bystanders.

Novel patient-derived preclinical models of liver cancer.

Preclinical models of cancer based on the use of human cancer cell lines and mouse models have enabled discoveries that have been successfully translated into patients. And yet the majority of clinical trials fail, emphasising the urgent need to improve preclinical research to better interrogate the potential efficacy of each therapy and the patient population most likely to benefit. This is particularly important for liver malignancies, which lack highly efficient treatments and account for hundreds of thousands of deaths around the globe.

Reflectance confocal microscopy for noninvasive examination of nonmelanocytic tumors and virus-associated skin lesions in organ transplant recipients.

Background: Drug-induced immunosuppression is necessary to prevent rejection of the foreign organ in transplanted patients, but neoplastic and virus-associated skin diseases are frequent complications. Reflectance confocal microscopy (RCM) recently emerged as a promising tool for the early diagnosis of skin lesions.

Materials And Methods: A total of 61 skin lesions, among them 20 basal cell carcinomas, six Bowen's diseases, 23 actinic keratoses, and 12 verrucae, were analyzed.

An Immune Gene Expression Signature Associated With Development of Human Hepatocellular Carcinoma Identifies Mice That Respond to Chemopreventive Agents.

Background & Aims: Cirrhosis and chronic inflammation precede development of hepatocellular carcinoma (HCC) in approximately 80% of cases. We investigated immune-related gene expression patterns in liver tissues surrounding early-stage HCCs and chemopreventive agents that might alter these patterns to prevent liver tumorigenesis.

Methods: We analyzed gene expression profiles of nontumor liver tissues from 392 patients with early-stage HCC (training set, N = 167 and validation set, N = 225) and liver tissue from patients with cirrhosis without HCC (N = 216, controls) to identify changes in expression of genes that regulate the immune response that could contribute to hepatocarcinogenesis.