Glycogen accumulation and phase separation drives liver tumor initiation

Liu, Qingxu; Li, Jiaxin; Zhang, Weiji; Xiao, Chen; Zhang, Shihao; Cheng, Ning; Li, Junhong; Su, Dongxue; Chen, Lihong; Zhao, Qian; Shao, Hui; Zhao, Hao; Chen, Qinghua; Li, Yuxi; Geng, Jing; Hong, Lian; Lin, Shuhai; Wu, Qiao; Deng, Xianming; Ke, Rongqin; Ding, Jin; Johnson, Randy L.; Liu, Xiaolong; Chen, Lanfen; Zhou, Dawang

doi:10.1016/j.cell.2021.10.001

Cited by 130 publications

(81 citation statements)

References 86 publications

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“…If daHep is indeed a pre-malignant intermediate, it appears to be an early state prior to the establishment of large genomic instability and chromosomal rearrangements, a hallmark of hepatocarcinogenesis (Liu et al, 2020). In support of the pre-malignant hypothesis, a recent study showed that G6pc, a top down-regulated gene in daHep, is also greatly reduced in pre-malignant hepatic lesions, resulting in increased glycogen storage, a key metabolic adaptation in hepatocellular tumor initiation (Liu et al, 2021). Data from Liu et al also showed that the loss of G6pc accelerates HCC development, altogether suggesting that such a tumor-promoting metabolic switch may also be a feature of daHep and may potentially facilitate its malignant transformation.…”

Section: Discussionmentioning

confidence: 95%

Single Nucleus RNA Sequencing of Pre-Malignant Liver Reveals Disease-Associated Hepatocyte State with HCC Prognostic Potential

Carlessi

Denisenko

Boslem

et al. 2022

Preprint

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Current approaches to stage chronic liver diseases have limited utility to directly predict liver cancer risk. Here, we employed single nucleus RNA sequencing (snRNA-seq) to characterize the cellular microenvironment of healthy and chronically injured pre-malignant livers using two distinct mouse models. Analysis of 40,748 hepatic nuclei unraveled a previously uncharacterized disease-associated hepatocyte transcriptional state (daHep). These cells were absent in healthy livers, but were increasingly prevalent as chronic liver disease progressed towards hepatocarcinogenesis. Gene expression deconvolution of 1,439 human liver transcriptomes from publicly available datasets revealed that daHep frequencies highly correlate with current histopathological liver disease staging systems. Importantly, we show that high daHep levels precede carcinogenesis in mice and humans and predict a higher risk of hepatocellular carcinoma (HCC) development. This novel transcriptional signature with diagnostic and, more importantly, prognostic significance has the potential to change the way chronic liver disease patients are staged, surveilled and risk-stratified.

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Section: Discussionmentioning

confidence: 95%

Single Nucleus RNA Sequencing of Pre-Malignant Liver Reveals Disease-Associated Hepatocyte State with HCC Prognostic Potential

Carlessi

Denisenko

Boslem

et al. 2022

Preprint

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“…HCC is characterized by a deregulated metabolic activity, and it has been described that the accumulation of hepatic glycogen favors tumor development [ 34 ]. Therefore, we evaluated glycogen accumulation within preneoplastic lesions using PAS staining.…”

Section: Resultsmentioning

confidence: 99%

Quercetin Regulates Key Components of the Cellular Microenvironment during Early Hepatocarcinogenesis

et al. 2022

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Hepatocellular carcinoma (HCC) is a health problem worldwide due to its high mortality rate, and the tumor microenvironment (TME) plays a key role in the HCC progression. The current ineffective therapies to fight the disease still warrant the development of preventive strategies. Quercetin has been shown to have different antitumor activities; however, its effect on TME components in preneoplastic lesions has not been fully investigated yet. Here, we aimed to evaluate the effect of quercetin (10 mg/kg) on TME components during the early stages of HCC progression induced in the rat. Histopathological and immunohistochemical analyses showed that quercetin decreases the size of preneoplastic lesions, glycogen and collagen accumulation, the expression of cancer stem cells and myofibroblasts markers, and that of the transporter ATP binding cassette subfamily C member 3 (ABCC3), a marker of HCC progression and multi-drug resistance. Our results strongly suggest that quercetin has the capability to reduce key components of TME, as well as the expression of ABCC3. Thus, quercetin can be an alternative treatment for inhibiting the growth of early HCC tumors.

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“…At an early stage, glycogen accumulation and phase separation in liver tumors can activate YAP to drive liver tumor initiation. However, in advanced stages, YAP can be activated by a different mechanism, high levels of glucose, to promote tumor development ( 89 ). It is worth considering whether lncRNAs and TAMs are involved in such completely different YAP activation mechanisms in the early and late stages.…”

Section: Discussionmentioning

confidence: 99%

Crosstalk Among YAP, LncRNA, and Tumor-Associated Macrophages in Tumorigenesis Development

Liu

Zhang

et al. 2022

Front. Oncol.

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Long non-coding RNAs (ncRNAs), which do not encode proteins, regulate cell proliferation, tumor angiogenesis, and metastasis and are closely associated with the development, progression, and metastasis of many cancers. Tumor-associated macrophages (TAMs) in the tumor microenvironment play an important role in cancer progression. The Hippo signaling pathway regulates cell proliferation and apoptosis, maintains tissue and organ size, and homeostasis of the internal environment of organisms. Abnormal expression of Yes-associated protein (YAP), the Hippo signaling pathway key component, is widely observed in various malignancies. Further, TAM, lncRNA, and YAP are currently valuable targets for cancer immunotherapy. In this review, we have logically summarized recent studies, clarified the close association between the three factors and tumorigenesis, and analyzed the outlook of tumor immunotherapy.

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Glycogen accumulation and phase separation drives liver tumor initiation

Cited by 130 publications

References 86 publications

Single Nucleus RNA Sequencing of Pre-Malignant Liver Reveals Disease-Associated Hepatocyte State with HCC Prognostic Potential

Single Nucleus RNA Sequencing of Pre-Malignant Liver Reveals Disease-Associated Hepatocyte State with HCC Prognostic Potential

Quercetin Regulates Key Components of the Cellular Microenvironment during Early Hepatocarcinogenesis

Crosstalk Among YAP, LncRNA, and Tumor-Associated Macrophages in Tumorigenesis Development

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