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Gene expression profiling of CD8+ T cells in the Norathyriol versus PBS-treated co-culture system

ABSTRACT: Metabolic reprogramming fuels cancer cell metastasis and remodels the immunosuppressive tumor microenvironment (TME). We report here that a circRNA, circPETH, packaged by extracellular vesicles (EVs) from tumor-associated macrophages (TAMs) to hepatocellular carcinoma (HCC) cells, facilitates glycolysis and metastasis of recipient HCC cells. Mechanistically, circPETH-147aa, encoded by circPETH in a m6A-driven manner, promotes PKM2-catalyzed ALDOA-S36 phosphorylation via MEG pocket. Furthermore, circPETH-147aa impairs anti-HCC immunity by elevating HuR-dependent SLC43A2 mRNA stability and driving methionine and leucine deficiency in cytotoxic CD8+ T cells. Importantly, by virtual and experimental screening, we found that the novel small-molecule Norathyriol was an effective inhibitor that targets the MEG pocket on circPETH-147aa surface. Norathyriol reverses circPETH-147aa-facilitated acquisition of metabolic and metastatic phenotypes for HCC cells, increases anti-PD1 efficacy and boosts cytotoxic CD8+ T-cell function. Our findings determine Norathyriol as a promising anti-HCC agent that contributes to the attenuation of advanced HCC resistance to immune checkpoint blocker (ICB) therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE242130 | GEO | 2024/09/01

REPOSITORIES: GEO

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Gene expression profiling for circPETH overexpression and knockout

Project description:Metabolic reprogramming fuels cancer cell metastasis and remodels immunosuppressive tumor microenvironment (TME). We report here that a circRNA packaged by extracellular vesicles (EVs) from tumor-associated macrophages (TAMs) to hepatocellular carcinoma (HCC) cells, circPETH, facilitates glycolysis and metastasis of HCC cells. Mechanistically, circPETH-147aa, encoded by circPETH in m6A-driven manner, promotes the PKM2-catalyzed ALDOA-S36 phosphorylation via MEG pocket. Furthermore, circPETH-147aa impairs anti-HCC immunity by elevating the HuR-dependent SLC43A2-mRNA stability and stimulating the deficiency of methionine and leucine in cytotoxic CD8+ T cells. Importantly, we successfully identified a novel small molecule, Norathyriol, by virtual and experimental screening as an effective inhibitor targeting MEG pocket on circPETH-147aa surface. Norathyriol reverses circPETH-147aa-facilitated metabolic and metastatic phenotypes of HCC cells, improves anti-PD1 efficacy and boosts cytotoxic CD8+ T cells function. Our findings determine Norathyriol as a promising anti-HCC agent, and contribute to overcoming the resistance of advanced HCC to immune checkpoint blockades (ICBs) therapies.

2024-08-29 | GSE242016 | GEO

Aldolase A Accelerates Cancer Progression by Modulating mRNA Translation and Protein Biosynthesis via Noncanonical Mechanisms

Project description:We provide robust and intensive evidence highlighting a close cooperative mechanistic interaction between ALDOA and IGF2BP1 that fine-tunes mRNA translation and enhances liver cancer progression. Moreover, specifically targeting ALDOA with GalNAc-conjugated siRNA shows promising anti-HCC effect in vivo. our findings uncover a previously unappreciated function of ALDOA in modulating mRNA translation and highlight the potential of targeting ALDOA as a prospective therapeutic strategy in HCC.

2023-07-30 | GSE224922 | GEO

Loss-of-function genetic screening identifies ALDOA as an essential driver for hepatocellular carcinoma cell growth under hypoxia

Project description:Hypoxia is a common feature of tumor microenvironment (TME), which promotes tumor progression, metastasis and therapeutic drug resistance via a myriad of cell activities in tumor and stroma cells. While targeting hypoxic TME is emerging as a promising strategy for treating solid tumors, preclinical studies with this approach are lacking in hepatocellular carcinoma (HCC). From a genome-wide CRISPR/Cas9 gene knockout screening, we identified aldolase A (ALDOA), a key enzyme in glycolysis and gluconeogenesis, as a master driver for HCC cell growth under hypoxia. To delineate the functional implications of ALDOA in HCC, transcriptome sequencing is performed to interrogate the differential gene expression in ALDOA-knockdown HepG2 cells under hypoxia.

2021-06-28 | GSE168544 | GEO

Deciphering the Protein-Protein Interaction Network Regulating Hepatocelluler Carcinoma Metastasis

Project description:Hepatocellular carcinoma (HCC) is one of the leading causes of mortality related to cancer all over the world. The poor prognosis of HCC is mostly due to recurrence and tumor metastasis. In order to better understand the molecular mechanisms of HCC metastasis, we analyzed the proteome of three HCC cell lines with different metastasis potentials by using quantitative proteomics and bioinformatics analysis. As a result, we identified 331 cellular proteins potentially associated to HCC metastasis, and constructed a highly connected protein-protein interaction (PPI) network. Functional annotation of the network uncovered prominent pathways and key roles of these proteins, suggesting that metabolism and cytoskeleton biological progresses are greatly involved with HCC metastasis. Furthermore, integrative network analysis revealed a rich-club organization in the PPI network indicating a hub center of connections, including several well-known cancer related proteins, such as SRC proto-oncogene, non-receptor tyrosine kinase (SRC) and pyruvate kinase M2 (PKM2). Moreover, the differential expressions of two identified proteins, including PKM2 and actin-related protein 2/3 complex subunit 4 (ARPC4), were validated using Western blotting. These two proteins were identified as potential prognostic markers for HCC by using survival rate analysis.

2017-06-20 | PXD005647 | Pride

Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma

Project description:Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of pyruvate kinase, and PKM2 expression is closely linked to embryogenesis, tissue regeneration, and cancer. To interrogate the functional requirement for PKM2 during development and tissue homeostasis, we generated germline PKM2 null mice (Pkm2-/-). Unexpectedly, despite being the primary isoform expressed in most wild-type adult tissues, we found that Pkm2-/- mice are viable and fertile. Thus, PKM2 is not required for embryonic or postnatal development. Loss of PKM2 leads to compensatory expression of PKM1 in the tissues that normally express PKM2. Strikingly, PKM2 loss leads to spontaneous development of hepatocellular carcinoma (HCC) with high penetrance that is accompanied by progressive changes in systemic metabolism characterized by altered systemic glucose homeostasis, inflammation, and hepatic steatosis. Therefore, in addition to its role in cancer metabolism, PKM2 plays a role in controlling systemic metabolic homeostasis and inflammation, thereby preventing HCC by a non-cell-autonomous mechanism. RNA was isolated from flash frozen ground whole liver tissue of 35 week old PKM2 KO and WT mice. Three independent mice from each condition were used as biological replicates.

2016-03-25 | E-GEOD-79535 | biostudies-arrayexpress

Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma

2016-03-25 | GSE79535 | GEO

Macrophages Coated Tumor Cluster (MCTC) Aggravated Hepatoma Invasion and Immunotherapy Resistance via Entrapping Cytotoxic T Cells to Generate Local Immune Deprivation in a M2BP-dependent manner

Project description:Immune checkpoint inhibitors (ICIs) represent promising treatment for hepatocellular carcinoma (HCC) due to abundant lymphocyte infiltration. However, some HCC patients respond poorly to ICI therapy due to the presence of various immunosuppressive factors in tumor microenvironment. Our research revealed that macrophage-coated tumor clusters (MCTCs) signified a unique spatial structural organization in HCC, correlating with diminished recurrence-free survival (RFS) and overall survival (OS) in a total of 572 HCC cases from 3 internal cohorts and 2 external validation cohort independently. Mechanistically, Tumor-derived M2BP induced MCTCs formation, and entrapped immunocompetent cells at the edge of MCTCs to induce intratumoral cytotoxic T cells exclusion and local immune deprivation. Combined treatment of anti-PD-1 antibody and Mac-2 antagonist GB1107 before MCTC formation could significantly attenuated HCC growth and inhibited HCC metastasis in vivo by recovering intratumoral infiltration of cytotoxic T cells, offering a potential strategy to enhance ICI efficacy in HCC.

2024-06-12 | GSE248907 | GEO

RNA N6-methyladenosine methyltransferase METTL3 drives NAFLD-HCC and is a therapeutic target for boosting immunotherapy [m6A-seq]

Project description:Non-alcoholic fatty liver disease (NAFLD) is an emerging risk factor of hepatocellular carcinoma (HCC). However, the mechanism and target therapy on NAFLD-HCC are still unclear. Here, we identify that the N6-methyladenosine (m6A) methyltransferase METTL3 promotes NAFLD-HCC. Hepatocyte-specific Mettl3 knockin exacerbated NAFLD-HCC formation while Mettl3 knockout exerted an opposite effect in mice. Single-cell RNA-seq revealed that METTL3 suppressed antitumor immune response by reducing infiltration of Gzmb+ and IFN-γ+ CD8+ T-cell, thereby facilitating immune escape. Mechanistically, METTL3 mediates SCAP mRNA m6A to promote its translation, leading to the activation of cholesterol biosynthesis. This enhanced secretion of cholesterol and cholesteryl esters, lipotoxins that impaired CD8+ T cell function in tumor microenvironment. Targeting of METTL3 by sgRNA, nanoparticle-siRNA, or pharmacological inhibitor (STM2457) in combination with anti-PD1 synergized to reinvigorate cytotoxic CD8+ T cells and mediate tumor regression. Together, METTL3 is a therapeutic target in NAFLD-HCC, especially in conjunction with immune checkpoint blockade (ICB) therapy.

2023-08-23 | GSE233807 | GEO

RNA N6-methyladenosine methyltransferase METTL3 drives NAFLD-HCC and is a therapeutic target for boosting immunotherapy [RNA-Seq]

2023-08-23 | GSE233806 | GEO

Lenvatinib recruits cytotoxic GZMK+CD8 T cells in hepatocellular carcinoma

Project description:Lenvatinib targets multiple oncogenic kinases including vascular endothelial growth factor receptors (VEGFRs) and showed longer median progression-free survival than sorafenib, the only approved treatment for >10 years. With the successful combination therapy of anti-PD-L1 pembrolizumab and anti-VEGF bevacizumab for advanced HCC as well as encouraging experimental findings, lenvatinib was also expected to enhance anti-tumor effects by combining anti-PD-1 pembrolizumab compared to lenvatinib alone; however, the phase III clinical trial failed to show their synergetic survival benefits, highlighting the need for elucidating its mode of action in human HCC specimens after lenvatinib treatment. We performed multi-layer transcriptome analyses of surgically resected human HCC samples after lenvatinib treatment as a neo-adjuvant therapy using RNA-sequencing. Molecular pathway analyses and immunohistochemistry revealed that VEGF-mediated aberrant vascularity and cytotoxic GZMK+CD8 T cells infiltration were significantly improved in lenvatinib-treated HCC; however, the majority of these cytotoxic T cells were trapped in the intratumor fibrotic stroma, suggesting that lenvatinib-treated HCC is in the so-called excluded condition. Excluded tumors are generally believed to be less responsive to immune checkpoint inhibitors, which might be the reason the combination therapy failed to show the additive benefits.

2023-08-08 | GSE223201 | GEO

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