References of "Presta, Luana 50031481"
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See detailFocal adhesion kinase plays a dual role in TRAIL resistance and metastatic outgrowth of malignant melanoma
Del Mistro, Greta; Riemann, Shamala; Schindler, Sebastian et al

in Cell Death and Disease (2022)

Despite remarkable advances in therapeutic interventions, malignant melanoma (MM) remains a life-threating disease. Following high initial response rates to targeted kinase-inhibition metastases quickly ... [more ▼]

Despite remarkable advances in therapeutic interventions, malignant melanoma (MM) remains a life-threating disease. Following high initial response rates to targeted kinase-inhibition metastases quickly acquire resistance and present with enhanced tumor progression and invasion, demanding alternative treatment options. We show 2nd generation hexameric TRAIL-receptor-agonist IZI1551 (IZI) to effectively induce apoptosis in MM cells irrespective of the intrinsic BRAF/NRAS mutation status. Conditioning to the EC50 dose of IZI converted the phenotype of IZI-sensitive parental MM cells into a fast proliferating and invasive, IZI-resistant metastasis. Mechanistically, we identified focal adhesion kinase (FAK) to play a dual role in phenotype-switching. In the cytosol, activated FAK triggers survival pathways in a PI3K- and MAPK-dependent manner. In the nucleus, the FERM domain of FAK prevents activation of wtp53, as being expressed in the majority of MM, and consequently intrinsic apoptosis. Caspase-8-mediated cleavage of FAK as well as FAK knockdown, and pharmacological inhibition, respectively, reverted the metastatic phenotype-switch and restored IZI responsiveness. FAK inhibition also re-sensitized MM cells isolated from patient metastasis that had relapsed from targeted kinase inhibition to cell death, irrespective of the intrinsic BRAF/NRAS mutation status. Hence, FAK-inhibition alone or in combination with 2nd generation TRAIL-receptor agonists may be recommended for treatment of initially resistant and relapsed MM, respectively. [less ▲]

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See detailEGFR-induced suppression of HPV E6/E7 is mediated by microRNA-9-5p silencing of BRD4 protein in HPV-positive head and neck squamous cell carcinoma.
Nantajit, Danupon; Presta, Luana UL; Sauter, Thomas UL et al

in Cell death & disease (2022), 13(11), 921

EGFR upregulation is an established biomarker of treatment resistance and aggressiveness in head and neck cancers (HNSCC). EGFR-targeted therapies have shown benefits for HPV-negative HNSCC; surprisingly ... [more ▼]

EGFR upregulation is an established biomarker of treatment resistance and aggressiveness in head and neck cancers (HNSCC). EGFR-targeted therapies have shown benefits for HPV-negative HNSCC; surprisingly, inhibiting EGFR in HPV-associated HNSCC led to inferior therapeutic outcomes suggesting opposing roles for EGFR in the two HNSCC subtypes. The current study aimed to understand the link between EGFR and HPV-infected HNSCC particularly the regulation of HPV oncoproteins E6 and E7. We demonstrate that EGFR overexpression suppresses cellular proliferation and increases radiosensitivity of HPV-positive HNSCC cell lines. EGFR overexpression inhibited protein expression of BRD4, a known cellular transcriptional regulator of HPV E6/E7 expression and DNA damage repair facilitator. Inhibition of EGFR by cetuximab restored the expression of BRD4 leading to increased HPV E6 and E7 transcription. Concordantly, pharmacological inhibition of BRD4 led to suppression of HPV E6 and E7 transcription, delayed cellular proliferation and sensitised HPV-positive HNSCC cells to ionising radiation. This effect was shown to be mediated through EGFR-induced upregulation of microRNA-9-5p and consequent silencing of its target BRD4 at protein translational level, repressing HPV E6 and E7 transcription and restoring p53 tumour suppressor functions. These results suggest a novel mechanism for EGFR inhibition of HPV E6/E7 oncoprotein expression through an epigenetic pathway, independent of MAPK, but mediated through microRNA-9-5p/BRD4 regulation. Therefore, targeting EGFR may not be the best course of therapy for certain cancer types including HPV-positive HNSCC, while targeting specific signalling pathways such as BRD4 could provide a better and potentially new treatment to improve HNSCC therapeutic outcome. [less ▲]

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See detailProject-based learning course on metabolic network modelling in computational systems biology.
Sauter, Thomas UL; Bintener, Tamara; Kishk, Ali UL et al

in PLoS computational biology (2022), 18(1), 1009711

Project-based learning (PBL) is a dynamic student-centred teaching method that encourages students to solve real-life problems while fostering engagement and critical thinking. Here, we report on a PBL ... [more ▼]

Project-based learning (PBL) is a dynamic student-centred teaching method that encourages students to solve real-life problems while fostering engagement and critical thinking. Here, we report on a PBL course on metabolic network modelling that has been running for several years within the Master in Integrated Systems Biology (MISB) at the University of Luxembourg. This 2-week full-time block course comprises an introduction into the core concepts and methods of constraint-based modelling (CBM), applied to toy models and large-scale networks alongside the preparation of individual student projects in week 1 and, in week 2, the presentation and execution of these projects. We describe in detail the schedule and content of the course, exemplary student projects, and reflect on outcomes and lessons learned. PBL requires the full engagement of students and teachers and gives a rewarding teaching experience. The presented course can serve as a role model and inspiration for other similar courses. [less ▲]

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See detailImportance of the biomass formulation for cancer metabolic modeling and drug prediction.
Moscardo Garcia, Maria UL; Pires Pacheco, Maria Irene UL; Bintener, Tamara Jean Rita UL et al

in iScience (2021), 24(10), 103110

Genome-scale metabolic reconstructions include all known biochemical reactions occurring in a cell. A typical application is the prediction of potential drug targets for cancer treatment. The precision of ... [more ▼]

Genome-scale metabolic reconstructions include all known biochemical reactions occurring in a cell. A typical application is the prediction of potential drug targets for cancer treatment. The precision of these predictions relies on the definition of the objective function. Generally, the biomass reaction is used to illustrate the growth capacity of a cancer cell. Today, seven human biomass reactions can be identified in published metabolic models. The impact of these differences on the metabolic model predictions has not been explored in detail. We explored this impact on cancer metabolic model predictions and showed that the metabolite composition and the associated coefficients had a large impact on the growth rate prediction accuracy, whereas gene essentiality predictions were mainly affected by the metabolite composition. Our results demonstrate the importance of defining a consensus biomass reaction compatible with most human models, which would contribute to ensuring the reproducibility and consistency of the results. [less ▲]

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