Cancer-associated Fibroblast-derived SPP1 is a Potential Target for Overcoming Sorafenib and Lenvatinib Resistance in Hepatocellular Carcinoma
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ABSTRACT:
PROVIDER: PRJNA793786 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17408820_1.fastq.gz | Fastqsanger.gz | |||
| SRR17408820_2.fastq.gz | Fastqsanger.gz | |||
| SRR17408821_1.fastq.gz | Fastqsanger.gz | |||
| SRR17408821_2.fastq.gz | Fastqsanger.gz | |||
| SRR17408822_1.fastq.gz | Fastqsanger.gz |
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Project description:Abstract: Cancer-associated fibroblasts (CAFs) play an important role in the induction of chemo-resistance. The objectives of this study were to clarify the mechanism underlying CAF-mediated sorafenib/lenvatinib resistance and identify a novel therapeutic target to overcome resistance to sorafenib/lenvatinib in hepatocellular carcinoma (HCC). Methods: Whole transcriptome sequencing (WTS) data of nine pairs of CAFs and para-cancer-associated fibroblasts (PAFs) were analyzed to identify key molecules that induce resistance to tyrosine kinase inhibitors (TKIs). In vitro and in vivo experiments were performed to validate selected targets and related mechanisms. Plasma secreted phosphoprotein 1 (SPP1) expression levels prior to sorafenib/lenvatinib treatment as well as progression-free survival (PFS) and overall survival (OS) of an advanced HCC cohort (n=42) were evaluated using Kaplan–Meier analysis. Results: Co-culturing CAFs and HCC cells significantly reduced the responsiveness of HCC cells to sorafenib/lenvatinib, in vitro and in vivo. Systematic integrative analysis of the WTS data of CAFs/PAFs and publicly available gene expression data indicated that CAF-derived SPP1 (CAF-SPP1) was suitable for use as a candidate molecule to induce sorafenib/lenvatinib resistance. An evaluation of the mechanisms involved indicated that CAF-SPP1 increased phosphorylation of PKCɑ, which then activated rapidly accelerated fibrosarcoma (RAF)-extracellular signal-related kinase 1/2-signal transducer and activator of transcription 3 (STAT3) and phosophoinositide 3-kinase (PI3K)-AKT-mechanistic target of rapamycin kinase (mTOR) in HCC cells. SPP1 inhibitors reversed CAF-induced sorafenib/lenvatinib resistance in vitro and in vivo. Patients showing high plasma SPP1 prior to sorafenib/lenvatinib treatment exhibited significantly poor PFS (P=0.005) and OS (P=0.041). Conclusions: CAF-SPP1 enhances sorafenib/lenvatinib resistance in HCC by alternatively activating oncogenic pathways via PKCɑ phosphorylation. Inhibition of CAF-SPP1 may be utilized as a therapeutic strategy against TKI resistance in HCC. Plasma SPP1 level prior to TKI treatment shows potential as a promising biomarker for predicting sorafenib/lenvatinib response in advanced HCC patients.
2022-12-24 | GSE192912 | GEO
Project description:Hepatocellular carcinoma (HCC) activates platelets through the action of adjacent sinusoidal cells. Activated platelets bind to tumor-associated endothelial cells and release growth factors that promote tumor progression. We hypothesized that tumor inhibitors encapsulated in platelets would function as drug carriers for tumor therapy. We propose a therapeutic strategy for HCC using autologous platelets encapsulating multiple tyrosine kinase inhibitors in a rat chemically-induced HCC model. Sorafenib or lenvatinib was encapsulated in platelets isolated from tumor-bearing rats in vitro. The rats were divided into groups that received repeated intravenous injections (twice a week for 10 weeks) of the following materials: placebo, sorafenib (SOR), lenvatinib (LEN), autologous platelets, autologous platelets encapsulating sorafenib (SOR-PLT), and autologous platelets encapsulating lenvatinib (LEN-PLT). The therapeutic effect was then analyzed by ultrasonography (US) and histopathological analysis. Histopathological and US analysis demonstrated extensive tumor necrosis in the tumor tissue of SOR-PLT or LEN-PLT, but not in other experimental groups. By liquid chromatography-mass spectrometry, more abundant sorafenib was detected in tumor tissues after SOR-PLT administration than in surrounding normal tissues, but no such difference in sorafenib level was observed with SOR administration. Therefore, the use of autologous platelets encapsulating drugs might be a novel therapeutic strategy for HCC. We investigated the effect of the drug encapsulation process on the degradation of resident mRNA inherited from megakaryocytes in platelets.
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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
Project description:Sorafenib, the first targeted therapy for hepatocellular carcinoma (HCC), has been utilized in clinics over a decade. However, its effectiveness is severely hindered by the acquired drug resistance, the mechanisms of which remain largely elusive. In this study, we identify that carbonic anhydrase 2 (CA2) is a key regulator of sorafenib resistance. Mechanistically, sorafenib treatment decreases intracellular pH (pHi) by suppressing monocarboxylate transporter 4 (MCT4) expression, while high levels of CA2 counteract MCT4-mediated pHi dysregulation upon sorafenib treatment, maintaining pHi homeostasis to facilitate cell survival and sorafenib resistance. Targeting CA2 re-sensitizes resistant HCC cells to sorafenib both in vitro and in vivo. Importantly, analysis of clinical samples demonstrates a strong correlation between CA2 expression levels and the therapeutic efficacy of sorafenib in HCC patients. Our findings highlight the significance of CA2 in facilitating sorafenib resistance and propose targeting CA2 as a potential strategy for overcoming sorafenib resistance in HCC patients.
2024-10-24 | PXD056884 | Pride
Project description:Many cases of advanced hepatocellular carcinoma (HCC) are resistant to the widely used drug sorafenib, which worsens prognosis. While many studies have explored how acquired resistance emerges during drug exposure, the mechanism underlying primary resistance before treatment still remain elusive. Here, we performed single-cell lineage tracing and RNA sequencing to identify sorafenib-resistant lineages in HCC, and demonstrated that high expression of S100A14 was positively associated with primary sorafenib resistance. Knocking down S100A14 rendered xenograft tumors in mice significantly more sensitive to sorafenib. Mechanistic studies indicated that S100A14 binds to glutaminase and blocks its phosphorylation at residues Y308 and S314, which in turn inhibits its ubiquitination and subsequent degradation. This stabilization of glutaminase reduces oxidative stress in HCC cells and thereby antagonizes the ability of sorafenib to induce apoptosis. Inhibiting glutaminase with telaglenastat (CB-839) significantly improved sorafenib efficacy against xenograft tumors in vivo. These results suggest that S100A14 can contribute to primary sorafenib resistance in HCC by stabilizing glutaminase. Thus, analyzing the expression of S100A14 may be useful for predicting primary sorafenib resistance, and inhibiting S100A14 or glutaminase may be effective for preventing or overcoming such resistance.
2025-03-02 | GSE282234 | GEO
Project description:To understand the role of HIF1a in lenvatinib resistance, we conducted label-free quantitative proteome analysis in both control and lenvatinib resistance cell lines. This analysis revealed changes in the proteome due to the lenvatinib resistance, providing a valuable reference for further investigations.
2024-08-20 | PXD054805 | Pride
Project description:To investigate the mechanism of lenvatinib resistance, we established the lenvatinib resistant Huh7 (Huh7 LR) cells by continuous exposuring to lenvatinib (1–20 μM) for approximately 10 months. We then performed gene expression profiling analysis using data obtained from RNA-seq of Huh7 parental (Huh7 P) cells and the lenvatinib resistant Huh7 (Huh7 LR) cells.
2022-08-26 | GSE211850 | GEO
Project description:Treatment of hepatocellular carcinoma with autologous platelets encapsulating sorafenib or lenvatinib: a novel therapy exploiting tumor-platelet interactions
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Project description:Lenvatinib is a multiple receptor tyrosine kinases inhibitor (TKI) authorized for first-line treatment of hepatocellular carcinoma (HCC). However, Lenvatinib resistance is common in HCC clinical treatment, highlighting the urgent need to understand mechanisms of resistance. Here, we identified Golgi membrane protein 1 (GOLM1), a type II transmembrane protein originally located in the Golgi apparatus, as a novel regulator of Lenvatinib resistance. We established Lenvatinib resistance in human HCC cell lines PLC/PRF/5. Through RNA-seq, we found that GOLM1 was significantly upregulated, which was further validated in patients derived tumor tissue and peripheral blood. GOLM1 overexpression contributes to Lenvatinib resistance and HCC progression in vitro and in vivo. Mechanistically, GOLM1 upregulates CSN5 expression through EGFR-STAT3 pathway. Reversely, CSN5 deubiquitinates and stabilizes GOLM1 protein by inhibiting ubiquitin-proteasome pathway of GOLM1. Collectively, our data demonstrate that GOLM1 is one of the key driver of Lenvatinib resistance in HCC and depicts a molecular network in Lenvatininb resistant HCC cells.
2024-08-07 | GSE273819 | GEO
Project description:Rates of hepatocellular carcinoma (HCC) are increasing rapidly due to the epidemic of metabolic dysfunction-associated steatohepatitis (MASH). In addition to increased incidence, emerging evidence suggests that MASH driven HCC is associated with poor survival outcomes potentially due to the complex liver microenvironment which is characterized by hypoxia, steatosis, and fibrosis. Lenvatinib, is a multi-tyrosine kinase inhibitor, that is a standard of care therapy for unresected HCC, but 5-year survival rates are less than 20%. Therefore, developing treatments that inhibit cancer growth kinetics and target the tumor microenvironment to improve the therapeutic response in MASH-HCC are needed. Salsalate is a rheumatoid arthritis therapy that stimulates the AMP-activated protein kinase (AMPK) increasing fatty acid oxidation while reducing de-novo lipogenesis, fibrosis and cell proliferation pathways. Thus, we hypothesized that Salsalate could improve the therapeutic efficacy of Lenvatinib in MASH-HCC. In the current study, we show that treatment of human HCC cells with clinically relevant concentrations of Lenvatinib and Salsalate synergistically suppress proliferation and clonogenic survival, activate AMPK and inhibit the mTOR-HIF1a and Erk1/2 signaling pathways. In orthotopic xenograft and MASH-HCC mouse models Lenvatinib and Salsalate combination therapy suppressed angiogenesis and steatosis and fibrosis. RNA-sequencing revealed combination therapy enhanced mitochondria fatty acid oxidation and suppressed glycolysis, angiogenesis, fibrosis and cell cycle progression with regulatory network analysis suggesting a potential role for Activating transcription factor 3 (ATF3) and ETS-proto-oncogene-1 (ETS1). These data suggest that Lenvatinib and Salsalate combination therapy may have therapeutic potential for MASH-HCC due to effective metabolic rewiring and growth inhibition, leading to improvements in the liver microenvironment and inhibition of HCC proliferation.
2025-02-01 | GSE282660 | GEO