IGF2 is an epi-driver and therapeutic target in hepatocellular carcinoma
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ABSTRACT:
PROVIDER: PRJNA338010 | ENA |
REPOSITORIES: ENA
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Project description:Background & Aims: Hepatocellular carcinoma (HCC) is a major health problem. Most patients are diagnosed at advanced stages when the only approved therapy is sorafenib. Consequently, there is an urgent need to develop effective treatments. IGF-signaling is aberrantly activated in HCC, but there is no clear understanding on the molecular drivers and potential therapeutic targets within the pathway. Since IGF2-ligand is overexpressed in HCC, we aimed to elucidate its mechanism of overexpression, assess its oncogenic potential in vitro and in vivo and determine the antitumoral efficacy of molecular therapies against IGF2. Methods: Expression profiling, miRNAs expression and methylation were analyzed in 228 HCCs focusing on IGF2. Stable HCC cell lines with knock-down and ectopic overexpression of IGF2 were generated. A chemically-induced mouse model of HCC, and genetically-engineered mouse models (GEMM) overexpressing IGF2 in the liver were generated to assess IGF2 oncogenicity. The therapeutic potential of the monoclonal antibody against IGF-ligands (IGF1/2-mAb) and its combination with sorafenib was tested in vitro and in a xenograft model. Results: IGF2-overexpression occurred in 15% of HCC patients as a result of the epigenetic reactivation of IGF2-fetal promoters, mainly through loss of promoter methylation. Re-expression of IGF2 was associated with progenitor cell-like and poorly differentiated HCCs, and with poor prognosis (p<0.0001). In the GEMM model, IGF2-overexpression accelerated HCC progression and reduced survival (p=0.02). Conversely, IGF2-blockage using IGF1/2- mAbs delayed tumor growth and increased survival in vivo (p<0.0001), through antiproliferative and antiangiogenic mechanisms. Conclusions: We propose IGF2 as the first actionable epi-driver in HCC, and IGF1/2-mAbs as a potential targeted therapy in a defined subset of HCC patients. Keywords: IGF2, HCC, epidriver, IGF-pathway, monoclonal antibody, BI 836845.
2019-08-05 | GSE85274 | GEO
Project description:A Therapeutic Vaccine for Fibrolamellar Hepatocellular Carcinoma
| PRJNA1234708 | ENA
Project description:A Therapeutic Vaccine for Fibrolamellar Hepatocellular Carcinoma
| PRJNA1234707 | ENA
Project description:Identification of Driver Genes in Hepatocellular Carcinoma by Exome Sequencing
| PRJNA193570 | ENA
Project description:We identified an enhancer element near IGF2 locus that is possibly involved with dopamine function and schizophrenia. A knockout mouse was generated for the enhancer element in the IGF2 locus. We then characterized the striatal synaptosomes ( i.e. biological fraction representing pre- post synaptic nerve terminal)by mass spectometry from WT and Igf2 enhancer KO mice.
2019-05-31 | PXD012786 | Pride
Project description:The transcription factor nuclear factor-κB (NF-κB) has important roles for tumorigenesis, but how it regulates cancer stem cells (CSCs) remains largely unclear. We identified insulin-like growth factor 2 (IGF2) is a key target of NF-κB activated by HER2/HER3 signaling to form tumor spheres in breast cancer cells. The IGF2 receptor, IGF1 R, was expressed at high levels in CSC-enriched populations in primary breast cancer cells. Moreover, IGF2-PI3K (IGF2-phosphatidyl inositol 3 kinase) signaling induced expression of a stemness transcription factor, inhibitor of DNA-binding 1 (ID1), and IGF2 itself. ID1 knockdown greatly reduced IGF2 expression, and tumor sphere formation. Finally, treatment with anti-IGF1/2 antibodies blocked tumorigenesis derived from the IGF1Rhigh CSC-enriched population in a patient-derived xenograft model. Thus, NF-κB may trigger IGF2-ID1-IGF2-positive feedback circuits that allow cancer stem-like cells to appear. Then, they may become addicted to the circuits. As the circuits are the Achilles' heels of CSCs, it will be critical to break them for eradication of CSCs.
2016-09-05 | GSE64073 | GEO
Project description:This study will evaluate longitudinal performance of Epi proColon with respect to test positivity, longitudinal adherence to Epi proColon screening, adherence to follow-up colonoscopy and diagnostic yield, as well as assay failure rates.
| 2249389 | ecrin-mdr-crc
Project description:Management of hepatoblastoma (HB), the most frequent pediatric liver cancer, is based on surgical resection and perioperative chemotherapy regimens. In this study, we aimed to identify actionable targets in HB and assess the efficacy of molecular therapies in preclinical models of HB. Paired tumor and adjacent tissues from 31 HBs and a validation set of 50 HBs were analyzed using RNA-seq, SNP, and methylation arrays. IGF2 overexpression was identified as the top targetable HB driver, present in 71% of HBs (22/31). IGF2high tumors displayed progenitor cell features and shorter recurrence-free survival. IGF2 overexpression was associated in 91% of cases with fetal promoter hypomethylation, ICR1 deregulation, 11p15.5 loss of heterozygosity or miR483-5p overexpression. The antitumor effect of xentuzumab (a monoclonal antibody targeting IGF1/2) alone or in combination with the conventional therapeutic agent cisplatin was assessed in HB cell lines, in PDX-derived HB organoids and in a xenograft HB murine model. The combination of xentuzumab with cisplatin showed strong synergistic antitumor effects in organoids and in IGF2high cell lines. In mice (n = 55), the combination induced a significant decrease in tumor volume and improved survival compared with cisplatin alone. These results suggest that IGF2 is an HB actionable driver and that, in preclinical models of HB, the combination of IGF1/2 inhibition with cisplatin induces superior antitumor effects than cisplatin monotherapy. Overall, our study provides a rationale for testing IGF2 inhibitors in combination with cisplatin in HB patients with IGF2 overexpression.
| S-EPMC10073300 | biostudies-literature
Project description:Background and aims: Insulin-like growth factor 2 (IGF2) is closely associated with the occurrence and development of primary and secondary muscle atrophy. This study investigates the role of IGF2 deficiency in inducing muscle atrophy using muscle-specific Igf2 knockout mice, aiming to provide theoretical basis and new concepts for growth hormone supplementation therapy in muscle atrophy. Methods: We analyzed Igf2 expression using the Tabula Muris single-cell database and generated muscle-specific Igf2 knockout mice using the Cre/LoxP system with Mck-cre transgenic mice. We characterized the phenotype and assessed muscle size and mass through external observation, dissection, H&E staining, and microCT scanning. Muscle function was evaluated using the Md3000 grip strength meter, treadmill tests for endurance and electromyography (EMG) for contraction force. Transcriptome sequencing was performed on muscle tissues to analyze the impact of Igf2 deletion on gene expression and pathways. Results: The Tabula Muris database confirmed high Igf2 expression in limb muscles, and we successfully developed muscle-specific Igf2 knockout (Igf2 cKO) mice. Analyses using MicroCT and H&E staining showed reduced muscle size, weight, and density in the gastrocnemius of Igf2 cKO mice versus controls. Grip strength tests using the Md3000 animal grip strength meter and treadmill tests assessing running endurance both indicated reduced physical performance in the Igf2 cKO group, with weakened grip strength and decreased running endurance distance and time. Electromyography (EMG) measurements disclosed a decrease in gastrocnemius muscle contraction force in the Igf2 cKO group. Transcriptome sequencing highlighted significant functional changes in muscle-related processes, RNA polymerase II transcription, and the PI3K pathway in the Igf2 cKO mice. Conclusions: Igf2 is highly expressed in skeletal muscle tissue. Muscle-specific Igf2 knockout mice exhibited reduced muscle size, weight, and density, weakened grip strength, decreased gastrocnemius muscle contraction force, and reduced running endurance distance and time. These findings suggest that IGF2 supplementation may be a potentially effective strategy for treating muscle atrophy.
2025-12-01 | GSE281658 | GEO
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