A Metabolic Switch Controlling Liver Cancer Evolution from Senescent NASH Hepatocytes
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE266447 | GEO | 2025/01/10
REPOSITORIES: GEO
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Project description:Hepatocellular carcinoma (HCC), the third most common cancer, originates from differentiated hepatocytes undergoing compensatory proliferation in livers damaged primarily by viruses or nonalcoholic steatohepatitis (NASH)1,2. While increasing HCC risk3, NASH also induces TP53-dependent hepatocyte senescence4. How this tumor-suppressive response is activated but eventually bypassed to license HCC progression is unknown. We identified the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) as a TP53 target, induced in senescent NASH hepatocytes but downregulated in most human HCCs. Initial FBP1 downregulation in disease-associated hepatocytes, whose accumulation precedes HCC development5, activates AKT to inhibits GSK3 substrate binding, thereby augmenting activation of NRF2 which accelerates FBP1 and TP53 degradation. Intrinsic NRF2 activation and FBP1 loss trigger overlapping transcriptomic responses that suppress senescence, enhance hepatocyte proliferation and metabolism, and enable NRAS- or NASH-induced hepatocarcinogenesis. This AKT-dependent metabolic switch, operative in mice and humans, controls NASH to HCC progression. Our results further suggest that NASH-related hepatocyte senescence is triggered by hypernutrition-induced single strand DNA breaks. Senescence reversal enables HCC progenitor expansion and somatic mutagenesis.
2024-07-15 | GSE240047 | GEO
Project description:Background: Senescent hepatocytes accumulate in parallel with fibrosis progression during NASH. The mechanisms that enable progressive expansion of nonreplicating cell populations and the significance of that process in determining NASH outcomes are unclear. Many types of senescing cells upregulate the THBD-PAR-1 signaling axis to remain viable. Vorapaxar, an FDA-approved PAR-1 inhibitor, blocks the activity of that pathway. We used vorapaxar to determine if and how THBD-PAR1 signaling promotes fibrosis progression in NASH. Methods: We evaluated the THBD-PAR1 pathway in liver biopsies from NAFLD patient cohorts with a spectrum of liver fibrosis. Chow fed mice were treated with viral vectors to over-express p16 specifically in hepatocytes and induce replicative senescence. Effects on the THBD-PAR-1 axis and regenerative capacity were assessed; the transcriptome of p16 over-expressing hepatocytes was characterized and we examined how conditioned medium from senescent but viable (dubbed ‘undead’) hepatocytes reprograms hepatic stellate cells. A genetically obese mouse model of NASH with little liver fibrosis, and a diet-induced mouse model of NASH with advanced fibrosis were treated with vorapaxar to determine effects on hepatocyte senescence and liver damage. Results: Inducing senescence up-regulates the THBD-PAR1 signaling axis in hepatocytes and induces their expression of fibrogenic factors, including hedgehog ligands. Hepatocyte THBD-PAR1 signaling increases in NAFLD and supports sustained hepatocyte senescence that limits effective liver regeneration and promotes maladaptive repair. Inhibiting PAR-1 signaling with vorapaxar interrupts this process, reduces the burden of ‘undead’ senescent cells, and safely improves NASH and fibrosis despite ongoing lipotoxic stress Conclusion: The THBD-PAR1 signaling axis is a novel therapeutic target for NASH because blocking this pathway prevents accumulation of senescing but viable hepatocytes that generate factors that promote maladaptive liver repair.
2023-03-01 | GSE204901 | GEO
Project description:Crosstalk between deregulated hepatocyte metabolism and cells within the tumour microenvironment, and consequent effects on liver tumourigenesis, are incompletely understood. We show here that hepatocyte specific loss of the gluconeogenic enzyme fructose 1,6-bisphosphatase 1 (FBP1) disrupts liver metabolic homeostasis and promotes tumour progression. FBP1 is universally silenced in both human and murine liver tumours, and hepatocyte-specific Fbp1 deletion results in steatosis, concomitant with activation and senescence of hepatic stellate cells (HSCs), exhibiting a senescence-associated secretory phenotype (SASP). Depleting senescent HSCs by senolytic treatment with dasatinib/quercetin or ABT-263 inhibits tumour progression. We further demonstrate that FBP1-deficient hepatocytes promote HSC activation by releasing HMGB1; blocking its release with the small molecule inflachromene limits FBP1-dependent HSC activation, subsequent SASP development, and tumour progression. Collectively, these findings provide genetic evidence for FBP1 as a metabolic tumour suppressor in liver cancer and establish a critical link between hepatocyte metabolism and HSC senescence that promotes tumour growth.
2020-03-02 | MSV000085045 | MassIVE
Project description:Metabolic activation of CD8+ and NKT-cells causes NASH and HCC through cross-talk with hepatocytes. Mice that devloped HCC or NASH were compared to work out genomic differences of the two diseases. In order to characterise the importance of CCR2 (activation of monocytes) in the development of NASH and HCC CCR2 double-mutant mice were compared to CCR2 wildtype mice.
2014-06-01 | E-MTAB-2469 | biostudies-arrayexpress
Project description:Hepatocellular carcinoma (HCC) is frequently characterized by metabolic and immune remodeling in the tumor microenvironment. We previously discovered that liver-specific deletion of fructose-1, 6-bisphphotase 1 (FBP1), a gluconeogenic enzyme ubiquitously suppressed in HCC tissues, promotes liver tumorigenesis, and induces metabolic and immune perturbations closely resembling human HCC. However, the underlying mechanisms remain incompletely understood. Here we reported that FBP1-deficient livers exhibit diminished amounts of natural killer (NK) cells and accelerated tumorigenesis. Using the diethylnitrosamine-induced HCC mouse model, we analyzed potential changes in the immune cell populations purified from control and FBP1-depleted livers and found that NK cells were strongly suppressed. Mechanistically, FBP1 attenuation in hepatocytes derepresses an EZH2-dependent transcriptional program to inhibit PKLR expression. This leads to reduced levels of PKLR cargo proteins sorted into hepatocyte-derived EVs, dampened activity of EV-targeted NK cells, and accelerated liver tumorigenesis. Our study demonstrated that hepatic FBP1 depletion promotes HCC-associated immune remodeling, partly through the transfer of hepatocyte-secreted, PKLR-attenuated EVs to NK cells.
2023-03-11 | PXD026822 | Pride
Project description: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 characterizing NASH-HCC compared to other HCC aetiologies. We collected 80 NASH-HCC and 125 NASH samples from 5 institutions. Expression array (n=53 NASH-HCC; n=74 NASH) and whole exome sequencing (n=50 NASH-HCC) data were compared to HCCs of other aetiologies (n=184). Three NASH-HCC mouse models were analysed with RNAseq/expression-array (n=20). ACVR2A was silenced in HCC cells and proliferation assessed by MTT and colony formation assays. Mutational profiling of NASH-HCC tumours revealed TERT-promoter (56%), CTNNB1 (28%), TP53 (18%) and ACVR2A (10%) as the most-frequently mutated genes. ACVR2A mutation rates were higher in NASH-HCC than in other HCC aetiologies (10% versus 3%, p<0.05). In vitro, ACVR2A silencing prompted a significant increase in cell proliferation in HCC cells. We identified a novel mutational signature (MutSig-NASH-HCC) significantly associated with NASH-HCC (16% vs 2% in viral/alcohol-HCC, p=0.03). Tumour mutational burden (TMB) was higher in non-cirrhotic than in cirrhotic NASH-HCCs (1.45 versus 0.94 mutations/Mb; p<0.0017). Compared to other aetiologies of HCC, NASH-HCCs were enriched in bile and fatty acid signalling, oxidative stress and inflammation, and presented a higher fraction of Wnt/TGF-β proliferation subclass tumours (42% versus 26%, p=0.01) and a lower prevalence of the CTNNB1 subclass. Compared to other aetiologies, NASH-HCC showed a significantly higher prevalence of immunosuppressive cancer field. In three murine models of NASH-HCC key features of human NASH-HCC were preserved. NASH-HCCs display unique molecular features including higher rates of ACVR2A mutations and the presence of a newly identified mutational signature.
2021-06-29 | GSE164760 | GEO
Project description:Immunotherapy has opened hitherto unknown possibilities to treat cancer. Whereas some cancer types (e.g. melanoma) can be efficiently treated, others lack measurable positive effects (e.g. PDAC). Moreover, stratification of responders/non-responders is only possible in some cancer types (e.g. melanoma). Hepatocellular carcinoma (HCC) has a dismal prognosis, limited treatment options and survival benefit, and represents a potential cancer entity for successful immunotherapy. Here, we investigated NASH-triggered HCC in the context PD-1-targeted immunotherapy. Using flow cytometry, single cell RNA sequencing, immunohistochemistry and mass spectrometric analyses, we found a progressive increase of CD8+PD-1+ effector T-cells with a unique profile of exhaustion and activation markers rising with murine and human NASH severity. Notably, late-stage HCC treatment with PD-1-targeted immunotherapy enhanced hepatic carcinogenesis in mice. Dissecting potential mechanisms of action during tumor-initiation and -progression we analyzed the effects of PD-1-targeted immunotherapy at HCC initiation. PD-1-targeted immunotherapy induced a pro-tumorigenic environment, enhanced necro-inflammation and increased NAFLD-activation score (NAS), leading to increased liver cancer incidence, tumor number and nodule size. In contrast, anti-CD8 or anti-CD8/anti-NK1.1 treatment reduced NAS and abrogated the development of liver cancer, thus identifying CD8+PD-1+ T-cells as drivers of liver cancer in NASH-triggered HCC. Increased apoptotic signaling, STAT3 phosphorylation and hepatic proliferation were detected in intra-tumoral liver tissue upon PD-1-targeted immunotherapy. In line, PD-1-/- mice challenged with a NASH diet displayed early onset of hepatocarcinogenesis, corroborating the pro-tumorigenic role of absent or reduced PD-1. Mechanistically PD-1-targeted immunotherapy mainly affected hepatic abundance of CD8+PD-1+ T-cells, instead of altering the quality of Tox+CXCR6+ expressing CD8+PD-1+TNF+CD39+Gzmb+ T-cells found in NASH livers, leading to an aggressive, pro-tumorigenic liver environment. Single-cell mapping of human NASH-, borderline NASH- or unaffected livers corroborated our preclinical NASH results. Moreover, in human NASH livers a correlation of hepatic CD8+, PD-1+, TNF+ T-cells with fibrosis and NASH severity was observed. Accordingly, HCC patients with NASH etiology display a sharp increase in intra- and peri-tumoral CD8+ PD-1+ T-cells. In a cohort of 65 patients recruited across 6 centers in Germany and Austria, patients with NAFLD/NASH-driven HCC responded worse to PD-1-targeted immunotherapy by Nivolumab or Pembrolizumab compared to non-NAFLD patients. This resulted in significant reduced overall survival, in trends of faster disease progression and reduced progression free survival. Histological analysis of livers derived from HCC patients treated with PD-1-targeted immunotherapy displayed high levels of intra and peri-tumoral CD8+ PD-1+ T-cells and Ki67+ hepatocytes. Taken together, these data indicate that PD-1-targeted immunotherapy induces immune-related adverse effects in NAFLD/NASH-driven HCC through CD8+PD-1+ T-cells. Our data call for stratification of HCC patients subjected to PD-1-targeted immunotherapy, with NAFLD being a negative predictor.
2021-03-03 | PXD017236 | Pride
Project description:ABSTRACT Rationale Premature senescence is conducive to aging and cardiovascular diseases. Nrf2 transcription factor, the master orchestrator of adoptive response to cellular stress, has been implicated in regulation of premature senescence in fibroblasts, neural and mesenchymal stem cells by transactivation of antioxidant gene expression. However, as we show here, human primary endothelial cells (ECs) devoid of Nrf2 and murine Nrf2 transcriptional knockout (tKO) aortas are senescent but do not encounter oxidative stress and damage, what contradicts this mechanism. Moreover, a molecular switch between normal, senescent and apoptotic fate remains unknown. Objective To elucidate the mechanism of Nrf2-related premature senescence of vascular system, to understand why Nrf2 deregulation does not cause oxidative stress exclusionary in ECs and to indicate a molecular switch determining ECs fate. Methods and Results Herein we evidence that ECs deficient in Nrf2 protein, or with limited Nrf2 activity in shear stress conditions, exhibit excessive S-nitrosylation of proteins. It is also a characteristic of Nrf2 tKO murine aortas, as determined by biotin switch assay in situ. Mass spectrometry analysis reveals that NOX4 is S-nitrosylated exclusively in ECs devoid of Nrf2. A functional role of S-nitrosylation is protection of ECs from death by inhibition of NOX4-mediated oxidative damage. As a result Nrf2-deficient ECs preserve oxidative balance but are redirected to premature senescence. The same phenotype is seen in Nrf2 tKO aortas. These effects are mediated by Keap1, a direct binding partner of Nrf2 and repressor of its transcriptional activity, remaining in cytoplasm unrestrained by Nrf2. S-nitrosylation, followed by senescence, can also be triggered in smooth muscle cells (SMCs) by EC-derived paracrine induction of iNOS. Conclusions Collectively, Keap1-dependent S-nitrosylation of NOX4 hampers oxidative detriment in ECs with disturbed Nrf2 signaling and may provide defence in the adjacent aortic cells. Overabundance of unrestrained Keap1 in the cytoplasm determines fate of ECs.
2020-08-12 | PXD013640 | Pride
Project description:The burden of senescent hepatocytes correlates with MASLD severity but mechanisms driving senescence, and how it exacerbates MASLD are poorly understood. Hepatocytes become senescent when Smoothened (Smo) is deleted to disrupt Hedgehog signaling. We aimed to determine if the secretomes of Smo-deficient hepatocytes perpetuate senescence to drive MASLD progression. RNA seq analysis confirmed that hepatocyte populations of MASLD livers are depleted of Smo(+) cells and enriched with senescent cells. When fed CDA-HFD, Smo(-) mice had lower antioxidant markers and developed worse DNA damage, senescence, MASH and liver fibrosis than Smo(+) mice. Sera and hepatocyte-conditioned medium from Smo(-) mice were depleted of thymidine phosphorylase (TP), a protein that maintains mitochondrial fitness. Treating Smo(-) hepatocytes with TP reduced senescence and lipotoxicity; inhibiting TP in Smo(+) hepatocytes had the opposite effects and exacerbated hepatocyte senescence, MASH, and fibrosis in CDA-HFD-fed mice.Therefore, we found that inhibiting Hedgehog signaling in hepatocytes promotes MASLD by suppressing hepatocyte production of proteins that prevent lipotoxicity and senescence.
2024-10-01 | GSE273523 | GEO
Project description:To determine whether FBP1 has previously unknown tumor suppressor activity, we immunoprecipitated FBP1 from Huh7 HCC cells and performed mass spectrometry analyses of FBP1 immunoprecipitants.
2024-03-12 | PXD050213 | Pride