Understanding tumour cell heterogeneity and its implication for immunotherapy in liver cancer using single-cell analysis

Heinrich, S.; Craig, Amanda; Ma, Lichun; Heinrich, Bernd; Greten, Tim F.; Wang, Xin Wei

doi:10.1016/j.jhep.2020.11.036

Cited by 67 publications

(47 citation statements)

References 139 publications

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“…Furthermore, amplification of the gene PTK2 is also observed in up to 20% of HCC, resulting in overexpression of its encoded protein focal adhesion kinase (FAK), which is an important driver of tumor proliferation and metastasis [ 61 ]. It is generally recognized in the field that personalized approaches are the way forward [ 62 ], but they are hampered as inadequate of current NGS-panels for defining druggable mutations in liver cancer. Important work shows that targeting specifically multiple kinases hold promise in liver cancer [ 63 ] but the technological approaches involved do for now not allow introduction of such strategies in routine care [ 64 ].…”

Section: Liver Cancermentioning

confidence: 99%

Drug Discovery in Liver Disease Using Kinome Profiling

Mamedov

Fuhler

et al. 2021

IJMS

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The liver is one of the most important organs, playing critical roles in maintaining biochemical homeostasis. Accordingly, disease of the liver is often debilitating and responsible for untold human misery. As biochemical nexus, with kinases being master regulators of cellular biochemistry, targeting kinase enzymes is an obvious avenue for treating liver disease. Development of such therapy, however, is hampered by the technical difficulty of obtaining comprehensive insight into hepatic kinase activity, a problem further compounded by the often unique aspects of hepatic kinase activities, which makes extrapolations from other systems difficult. This consideration prompted us to review the current state of the art with respect to kinome profiling approaches towards the hepatic kinome. We observe that currently four different approaches are available, all showing significant promise. Hence we postulate that insight into the hepatic kinome will quickly increase, leading to rational kinase-targeted therapy for different liver diseases.

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Section: Liver Cancermentioning

confidence: 99%

Drug Discovery in Liver Disease Using Kinome Profiling

Mamedov

Fuhler

et al. 2021

IJMS

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Section: Introductionmentioning

confidence: 99%

“…3 The emerging of immunotherapy, including immune checkpoint inhibitors, holds new promise for the treatment of HCC, but similar issues exist as well. 4,5 Therefore, it is still urgent to comprehensively investigate the mechanism of HCC development and progression, which may provide new perspectives to break the dilemma of HCC treatment. 6 Ferroptosis is a newly identified form of regulated cell death and is mainly driven by iron-mediated oxidative damage, excessive lipid peroxidation, and cell membrane damage.…”

Section: Introductionmentioning

confidence: 99%

“…These findings provide potential targets and strategies for anticancer treatment by targeting ferroptosis. Noticeably, increasing evidence points to the comprehensive interactions between ferroptosis and metabolic pathways, including: (1) Amino acid and glutathione metabolism: Limitation of cysteine reduces the biosynthesis of glutathione (GSH) and causes the depletion of GSH, which directly inhibits the activity and stability of GPX4 and thereby induces the ferroptosis; (2) Lipid metabolism: Lipid peroxidation of polyunsaturated fatty acids (PUFAs) is an important process for the execution of ferroptosis, and the abundance and localization of PUFAs also correlate with the extent of ferroptosis; (3) Iron metabolism: The transport, storage, and transition of the intracellular iron impact the accumulation of lipid peroxides and subsequent ferroptosis; (4) Other metabolic pathways such as the mevalonate, NADPH, and selenium metabolism.…”

Section: Introductionmentioning

confidence: 99%

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Prognostic Role and Potential Mechanisms of the Ferroptosis-Related Metabolic Gene Signature in Hepatocellular Carcinoma

Dai

et al. 2021

PGPM

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Purpose Ferroptosis, as a novel regulated cell death form, has a close interaction with metabolism, which is largely unknown in cancer. In the present study, we conducted a comprehensive analysis of ferroptosis-related metabolic genes to delineate the metabolic signatures induced by ferroptosis and evaluate its prognostic significance in hepatocellular carcinoma (HCC). Methods The ferroptosis-related metabolic genes (Fer-MRGs) were identified by correlation analyses with transcriptome data from The Cancer Genome Atlas and Gene Expression Omnibus. Then, univariate and the least absolute shrinkage and selection operator Cox regression analysis was used to establish a novel risk score model. Univariate and multivariate COX analyses were used to identify independent prognostic factors for overall survival (OS) of HCC, and a nomogram was developed. The Fer-MRGs’ expression was further evaluated by quantitative real-time polymerase chain reaction in HCC. Results A total of 77 metabolic genes were identified as Fer-MRGs, and 26 were found with prognostic values for OS of HCC. Then, a novel nine-gene (AKR1C3, ATIC, G6PD, GMPS, GNPDA1, IMPDH1, PRIM1, RRM2, and TXNRD1) risk score model was constructed. Survival analyses showed worse OS in high-risk patients both in the training and validation groups. The model was also identified as an independent prognostic factor for HCC, and a prognostic nomogram for OS was further established with superior discriminative capacity and prediction accuracy. Notably, close correlations were also identified between the risk score and the expression of immune checkpoint genes, immune subtypes of tumor, and susceptibility of HCC to chemotherapeutic agents. Finally, elevated expression of eight Fer-MRGs (except for IMPDH1) was further verified in 16 pairs of HCC tumor and adjacent tissues. Conclusion These results indicated the intense interaction between ferroptosis and metabolism, the significant role of ferroptosis-related MRGs, and the great potential of the novel risk score model for prognosis prediction in HCC.

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“…Hepatocellular Carcinoma (HCC) [1]. The authors describe the highly relevant finding that HCCs can be divided in a group with high diversity and a group with low diversity of sc RNA sequencing data and that the "high group" displays a significantly worse prognosis.…”

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confidence: 99%

Is tissue hypoxia the principal mechanism for immune evasion and malignant progression in hepatocellular carcinoma?

Cramer

Vaupel

2021

Journal of Hepatology

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Understanding tumour cell heterogeneity and its implication for immunotherapy in liver cancer using single-cell analysis

Cited by 67 publications

References 139 publications

Drug Discovery in Liver Disease Using Kinome Profiling

Drug Discovery in Liver Disease Using Kinome Profiling

Prognostic Role and Potential Mechanisms of the Ferroptosis-Related Metabolic Gene Signature in Hepatocellular Carcinoma

Is tissue hypoxia the principal mechanism for immune evasion and malignant progression in hepatocellular carcinoma?

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