Relaxin gene delivery mitigates liver metastasis and synergizes with check point therapy.
Nature communications
Activated hepatic stellate cell (aHSC)-mediated liver fibrosis is essential to the development of liver metastasis. Here, we discover intra-hepatic scale-up of relaxin (RLN, an anti-fibrotic peptide) in response to fibrosis along with the upregulation of its primary receptor (RXFP1) on aHSCs. The elevated expression of RLN serves as a natural regulator to deactivate aHSCs and resolve liver fibrosis. Therefore, we hypothesize this endogenous liver fibrosis repair mechanism can be leveraged for liver metastasis treatment via enforced RLN expression. To validate the therapeutic potential, we utilize aminoethyl anisamide-conjugated lipid-calcium-phosphate nanoparticles to deliver plasmid DNA encoding RLN. The nanoparticles preferentially target metastatic tumor cells and aHSCs within the metastatic lesion and convert them as an in situ RLN depot. Expressed RLN reverses the stromal microenvironment, which makes it unfavorable for established liver metastasis to grow. In colorectal, pancreatic, and breast cancer liver metastasis models, we confirm the RLN gene therapy results in significant inhibition of metastatic progression and prolongs survival. In addition, enforced RLN expression reactivates intra-metastasis immune milieu. The combination of the RLN gene therapy with PD-L1 blockade immunotherapy further produces a synergistic anti-metastatic efficacy. Collectively, the targeted RLN gene therapy represents a highly efficient, safe, and versatile anti-metastatic modality, and is promising for clinical translation.
10.1038/s41467-019-10893-8
Best practice guidelines in the psychosocial management of HPV-related head and neck cancer: recommendations from the European Head and Neck Cancer Society's Make Sense Campaign.
Reich M,Licitra L,Vermorken J B,Bernier J,Parmar S,Golusinski W,Castellsagué X,Leemans C R
Annals of oncology : official journal of the European Society for Medical Oncology
Over the past three decades, oral human papillomavirus (HPV) has been associated with an increase in the incidence of oropharyngeal squamous cell carcinoma (OPSCC) in several countries. Specialist oncologists in head and neck cancer are observing a wider range of demographics, sexual behaviours, and survival outcomes with their patients. Additionally, there are fewer smokers, consumers of alcohol, or people of lower socioeconomic status than in previous decades. In order to support patients, the European Head and Neck Society's Make Sense Campaign aims to promote best practice in the management of head and neck cancer through the delivery of counselling, psychological assessment, support with the patient experience following HPV-related cancer diagnosis, sexual impact (in terms of communication, behaviour and prevention), facilitating access to educational resources about HPV in head and neck squamous cell carcinoma and OPSCC, and early referral if necessary. New concerns about psychosocial distress and unmet psychosocial needs following diagnosis, therefore, exist throughout the disease and treatment periods. Oncologists treating patients with HPV-related head and neck cancer must integrate new parameters focused on infection risk transmission and sexual topics. The development and dissemination of best practice guidelines through The European Head and Neck Cancer Society Make Sense Campaign will help healthcare professionals to be more confident and resourceful in supporting patients with HPV-related head and neck cancer.
10.1093/annonc/mdw272
PKLR promotes colorectal cancer liver colonization through induction of glutathione synthesis.
The Journal of clinical investigation
Colorectal cancer metastasis to the liver is a major cause of cancer-related death; however, the genes and pathways that govern this metastatic colonization event remain poorly characterized. Here, using a large-scale in vivo RNAi screen, we identified liver and red blood cell pyruvate kinase (PKLR) as a driver of metastatic liver colonization. PKLR expression was increased in liver metastases as well as in primary colorectal tumors of patients with metastatic disease. Evaluation of a murine liver colonization model revealed that PKLR promotes cell survival in the tumor core during conditions of high cell density and oxygen deprivation by increasing glutathione, the primary endogenous antioxidant. PKLR negatively regulated the glycolytic activity of PKM2, the major pyruvate kinase isoenzyme known to regulate cellular glutathione levels. Glutathione is critical for metastasis, and we determined that the rate-limiting enzyme of glutathione synthesis, GCLC, becomes overexpressed in patient liver metastases, promotes cell survival under hypoxic and cell-dense conditions, and mediates metastatic liver colonization. RNAi-mediated inhibition of glutathione synthesis impaired survival of multiple colon cancer cell lines, and pharmacological targeting of this metabolic pathway reduced colonization in a primary patient-derived xenograft model. Our findings highlight the impact of metabolic reprogramming within the niche as metastases progress and suggest clinical potential for targeting this pathway in colorectal cancer.
10.1172/JCI83587
Differentiation therapy for hepatocellular carcinoma: Multifaceted effects of miR-148a on tumor growth and phenotype and liver fibrosis.
Jung Kwang Hwa,Zhang Jing,Zhou Chong,Shen Hong,Gagea Mihai,Rodriguez-Aguayo Cristian,Lopez-Berestein Gabriel,Sood Anil K,Beretta Laura
Hepatology (Baltimore, Md.)
UNLABELLED:The death rate from hepatocellular carcinoma (HCC) is increasing, and liver cancer is the second leading cause of cancer-related mortality worldwide. Most patients with HCC have underlying liver cirrhosis and compromised liver function, limiting treatment options. Cirrhosis is associated with cell dedifferentiation and expansion of hepatocholangiolar progenitor cells. We identified a microRNA signature associated with HCC and hepatocytic differentiation of progenitor cells. We further identified miR-148a as an inducer of hepatocytic differentiation that is down-regulated in HCC. MiR-148a-mimetic treatment in vivo suppressed tumor growth, reduced tumor malignancy and liver fibrosis, and prevented tumor development. These effects were associated with an increased differentiated phenotype and mediated by IκB kinase alpha/NUMB/NOTCH signaling. CONCLUSION:miR-148a is an inhibitor of the IκB kinase alpha/NUMB/NOTCH pathway and an inducer of hepatocytic differentiation that when deregulated promotes HCC initiation and progression. Differentiation-targeted therapy may be a promising strategy to treat and prevent HCC.
10.1002/hep.28367
The role of oral hygiene in head and neck cancer: results from International Head and Neck Cancer Epidemiology (INHANCE) consortium.
Annals of oncology : official journal of the European Society for Medical Oncology
BACKGROUND:Poor oral hygiene has been proposed to contribute to head and neck cancer (HNC) risk, although causality and independency of some indicators are uncertain. This study investigates the relationship of five oral hygiene indicators with incident HNCs. METHODS:In a pooled analysis of 8925 HNC cases and 12 527 controls from 13 studies participating in the International Head and Neck Cancer Epidemiology Consortium, comparable data on good oral hygiene indicators were harmonized. These included: no denture wear, no gum disease (or bleeding), <5 missing teeth, tooth brushing at least daily, and visiting a dentist ≥once a year. Logistic regression was used to estimate the effects of each oral hygiene indicator and cumulative score on HNC risk, adjusting for tobacco smoking and alcohol consumption. RESULTS:Inverse associations with any HNC, in the hypothesized direction, were observed for <5 missing teeth [odds ratio (OR) = 0.78; 95% confidence interval (CI) 0.74, 0.82], annual dentist visit (OR = 0.82; 95% CI 0.78, 0.87), daily tooth brushing (OR = 0.83, 95% CI 0.79, 0.88), and no gum disease (OR = 0.94; 95% CI 0.89, 0.99), and no association was observed for wearing dentures. These associations were relatively consistent across specific cancer sites, especially for tooth brushing and dentist visits. The population attributable fraction for ≤ 2 out of 5 good oral hygiene indicators was 8.9% (95% CI 3.3%, 14%) for oral cavity cancer. CONCLUSION:Good oral hygiene, as characterized by few missing teeth, annual dentist visits, and daily tooth brushing, may modestly reduce the risk of HNC.
10.1093/annonc/mdw224
A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development.
Boege Yannick,Malehmir Mohsen,Healy Marc E,Bettermann Kira,Lorentzen Anna,Vucur Mihael,Ahuja Akshay K,Böhm Friederike,Mertens Joachim C,Shimizu Yutaka,Frick Lukas,Remouchamps Caroline,Mutreja Karun,Kähne Thilo,Sundaravinayagam Devakumar,Wolf Monika J,Rehrauer Hubert,Koppe Christiane,Speicher Tobias,Padrissa-Altés Susagna,Maire Renaud,Schattenberg Jörn M,Jeong Ju-Seong,Liu Lei,Zwirner Stefan,Boger Regina,Hüser Norbert,Davis Roger J,Müllhaupt Beat,Moch Holger,Schulze-Bergkamen Henning,Clavien Pierre-Alain,Werner Sabine,Borsig Lubor,Luther Sanjiv A,Jost Philipp J,Weinlich Ricardo,Unger Kristian,Behrens Axel,Hillert Laura,Dillon Christopher,Di Virgilio Michela,Wallach David,Dejardin Emmanuel,Zender Lars,Naumann Michael,Walczak Henning,Green Douglas R,Lopes Massimo,Lavrik Inna,Luedde Tom,Heikenwalder Mathias,Weber Achim
Cancer cell
Concomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic instability are detectable in CLDs before any neoplastic changes occur. Accumulated levels of hepatocyte apoptosis determine and predict subsequent hepatocarcinogenesis. Proliferation-associated DNA damage is sensed by a complex comprising caspase-8, FADD, c-FLIP, and a kinase-dependent function of RIPK1. This platform requires a non-apoptotic function of caspase-8, but no caspase-3 or caspase-8 cleavage. It may represent a DNA damage-sensing mechanism in hepatocytes that can act via JNK and subsequent phosphorylation of the histone variant H2AX.
10.1016/j.ccell.2017.08.010
Acetylation of PGK1 promotes liver cancer cell proliferation and tumorigenesis.
Hu Hongli,Zhu Wenwei,Qin Jun,Chen Min,Gong Liyan,Li Long,Liu Xiangyuan,Tao Yongzhen,Yin Huiyong,Zhou Hu,Zhou Lisha,Ye Dan,Ye Qinghai,Gao Daming
Hepatology (Baltimore, Md.)
Phosphoglycerate kinase 1 (PGK1) is an important enzyme in the metabolic glycolysis pathway. In this study, we observed a significant overexpression of PGK1 in liver cancer tissues and a negative correlation between PGK1 expression and liver cancer patient survival. Furthermore, depletion of PGK1 dramatically reduced cancer cell proliferation and tumorigenesis, indicating an oncogenic role of PGK1 in liver cancer progression. Moreover, we identified acetylation at the K323 site of PGK1 as an important regulatory mechanism for promoting its enzymatic activity and cancer cell metabolism. And we further characterized P300/cyclic adenosine monophosphate response element binding protein-binding protein-associated factor (PCAF) and Sirtuin 7 as the enzymes regulating K323 acetylation from both directions in liver cancer cells. CONCLUSION:These findings demonstrate a novel regulation of PGK1 as well as its important role in liver cancer progression. (Hepatology 2017;65:515-528).
10.1002/hep.28887
Human primary liver cancer-derived organoid cultures for disease modeling and drug screening.
Nature medicine
Human liver cancer research currently lacks in vitro models that can faithfully recapitulate the pathophysiology of the original tumor. We recently described a novel, near-physiological organoid culture system, wherein primary human healthy liver cells form long-term expanding organoids that retain liver tissue function and genetic stability. Here we extend this culture system to the propagation of primary liver cancer (PLC) organoids from three of the most common PLC subtypes: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and combined HCC/CC (CHC) tumors. PLC-derived organoid cultures preserve the histological architecture, gene expression and genomic landscape of the original tumor, allowing for discrimination between different tumor tissues and subtypes, even after long-term expansion in culture in the same medium conditions. Xenograft studies demonstrate that the tumorogenic potential, histological features and metastatic properties of PLC-derived organoids are preserved in vivo. PLC-derived organoids are amenable for biomarker identification and drug-screening testing and led to the identification of the ERK inhibitor SCH772984 as a potential therapeutic agent for primary liver cancer. We thus demonstrate the wide-ranging biomedical utilities of PLC-derived organoid models in furthering the understanding of liver cancer biology and in developing personalized-medicine approaches for the disease.
10.1038/nm.4438
Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells.
Ma Chi,Han Miaojun,Heinrich Bernd,Fu Qiong,Zhang Qianfei,Sandhu Milan,Agdashian David,Terabe Masaki,Berzofsky Jay A,Fako Valerie,Ritz Thomas,Longerich Thomas,Theriot Casey M,McCulloch John A,Roy Soumen,Yuan Wuxing,Thovarai Vishal,Sen Shurjo K,Ruchirawat Mathuros,Korangy Firouzeh,Wang Xin Wei,Trinchieri Giorgio,Greten Tim F
Science (New York, N.Y.)
Primary liver tumors and liver metastasis currently represent the leading cause of cancer-related death. Commensal bacteria are important regulators of antitumor immunity, and although the liver is exposed to gut bacteria, their role in antitumor surveillance of liver tumors is poorly understood. We found that altering commensal gut bacteria in mice induced a liver-selective antitumor effect, with an increase of hepatic CXCR6 natural killer T (NKT) cells and heightened interferon-γ production upon antigen stimulation. In vivo functional studies showed that NKT cells mediated liver-selective tumor inhibition. NKT cell accumulation was regulated by CXCL16 expression of liver sinusoidal endothelial cells, which was controlled by gut microbiome-mediated primary-to-secondary bile acid conversion. Our study suggests a link between gut bacteria-controlled bile acid metabolism and liver antitumor immunosurveillance.
10.1126/science.aan5931