A5072917273- melanin and skin pigmentation
- RNA regulation and disease
- CRISPR and Genetic Engineering
- Cancer-related molecular mechanisms research
- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- Redox biology and oxidative stress
- Melanoma and MAPK Pathways
- RNA Research and Splicing
- Protein Degradation and Inhibitors
- Genomics, phytochemicals, and oxidative stress
- Endoplasmic Reticulum Stress and Disease
- Herpesvirus Infections and Treatments
- interferon and immune responses
- Immunotherapy and Immune Responses
VIB-KU Leuven Center for Cancer Biology
2020-2024
KU Leuven
2021
University of Patras
2021
The ability to adapt environmental stress, including therapeutic insult, contributes tumor evolution and drug resistance. In suboptimal conditions, the integrated stress response (ISR) promotes survival by dampening cytosolic translation. We show that ISR-dependent also relies on a concomitant up-regulation of mitochondrial protein synthesis, vulnerability can be exploited using mitoribosome-targeting antibiotics. Accordingly, such agents sensitized MAPK inhibition, thus preventing...
Abstract Tumor heterogeneity is a key feature of melanomas that hinders development effective treatments. Aiming to overcome this, we identified LINC00518 (LENOX; lincRNA-enhancer oxidative phosphorylation) as melanoma-specific lncRNA expressed in all known melanoma cell states and essential for survival vitro vivo. Mechanistically, LENOX promoted association the RAP2C GTPase with mitochondrial fission regulator DRP1, increasing DRP1 S637 phosphorylation, fusion, phosphorylation. expression...
Abstract Although immune checkpoint blockade (ICB) has revolutionized cancer treatment, resistance mechanisms limit its clinical benefit. Here we characterise LISRR , a cancer-specific lncRNA highly expressed in melanoma patients refractory to ICB. In cells undergoing (therapeutic) stress, recruits DAZAP1 (Deleted AZoospermia Associated Protein 1) polysomes and drives the assembly of subset ribosomes at endoplasmic reticulum, directing synthesis an immunosuppressive translatome. This...
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Summary Therapy resistance remains a major clinical challenge for the management of metastatic melanoma. Here we show that activation Integrated Stress Response (ISR), which is common in drug-tolerant and resistant melanoma, promotes selective synthesis mitochondrial proteins cytosol. Since translation adapts to influx nuclear-encoded proteins, ISR indirectly enhances makes these cells highly vulnerable inhibitors. Treatment melanoma with mitoribosome-targeting antibiotics, induces...
KRASG12C is among the most common oncogenic mutations in lung adenocarcinoma and a promising target for treatment by small-molecule inhibitors. KRAS signaling responsible modulation of tumor microenvironment, with translation factors being prominent deregulated targets. In present study, we used TALENs to edit EGFRWT CL1-5 A549 cells integration Tet-inducible expression system. Subsequent analysis both cell lines showed that cap-dependent was impaired via involvement mTORC2 NF-κB. contrast,...
Abstract Upregulation of mitochondrial respiration coupled with high ROS-scavenging capacity is a characteristic shared by drug-tolerant cells in several cancers. As translational fidelity essential for cell fitness, protection the and cytosolic ribosomes from oxidative damage pivotal. While mechanisms recognizing repairing such exist cytoplasm, corresponding process mitochondria remains unclear. By performing Ascorbate PEroXidase (APEX)-proximity ligation assay directed to matrix followed...
<div>Abstract<p>Tumor heterogeneity is a key feature of melanomas that hinders development effective treatments. Aiming to overcome this, we identified LINC00518 (LENOX; lincRNA-enhancer oxidative phosphorylation) as melanoma-specific lncRNA expressed in all known melanoma cell states and essential for survival <i>in vitro</i> vivo</i>. Mechanistically, LENOX promoted association the RAP2C GTPase with mitochondrial fission regulator DRP1, increasing DRP1 S637...
<div>Abstract<p>Tumor heterogeneity is a key feature of melanomas that hinders development effective treatments. Aiming to overcome this, we identified LINC00518 (LENOX; lincRNA-enhancer oxidative phosphorylation) as melanoma-specific lncRNA expressed in all known melanoma cell states and essential for survival <i>in vitro</i> vivo</i>. Mechanistically, LENOX promoted association the RAP2C GTPase with mitochondrial fission regulator DRP1, increasing DRP1 S637...
<p>LENOX overexpression promotes resistance to BRAF and glycolysis inhibition.</p>
<p>LENOX regulates mitochondrial morphology</p>
<p>Gain of LENOX function stimulates melanoma cell proliferation</p>
<p>LENOX and RAP2C knockdown induce mitochondrial dysfunction, release of reactive oxygen species (ROS), DNA damage cell cycle block</p>
<p>RAP2 paralog expression in melanoma cells</p>
<p>LENOX is required for xenograft growth</p>
<p>LENOX regulates melanoma cell proliferation and survival</p>
<p>LENOX overexpression promotes resistance to BRAF and glycolysis inhibition.</p>
<p>Legends to Supplementary Figures and Tables</p>
<p>Legends to Supplementary Figures and Tables</p>
<p>LENOX is associated with melanoma clinical features and regulated by TFAP2A.</p>
<p>Gain of LENOX function stimulates melanoma cell proliferation</p>
<p>MAPK inhibition increases LENOX expression downstream of TFAP2A.</p>
<p>LENOX regulates mitochondrial morphology</p>