Biology subjects

Crea, F.

Publications and source records attributed to Crea, F..

5 recordsLinked to original sources

bioRxiv2024

EHZ2 inhibition enhances the activity of platinum chemotherapy in aggressive variant prostate cancer

BackgroundEZH2 promotes aggressive-variant prostate cancer (AVPC) progression via histone H3-Lysine-27 tri-methylation (H3K27me3). We hypothesize that epigenetic reprogramming via EZH2 inhibitors (EZH2i) improves the efficacy of chemotherapy in AVPC. MethodsWe studied the expression of EZH2 in clinical prostate cancer cohorts (bioinformatics). We determined the effect of EZH2i on both cellular- and cell-free-H3K27me3 levels. We measured effects of carboplatin with/without EZH2i on AVPC cell viability (IC50). We studied how EZH2i modulate gene expression (RNA Seq). ResultsEZH2 was significantly up-regulated in AVPC vs other prostate cancer types. EZH2i reduced both cellular and cell free-H3K27me3 levels. EZH2i significantly reduced carboplatin IC50. EZH2i reduced the expression of DNA repair and increased the expression of pro-apoptotic genes. Article HighlightsO_LIPolycomb-mediated gene silencing promotes prostate cancer progression C_LIO_LIAggressive-variant prostate cancers (AVPCs) are characterized by increased activity of the Polycomb-Repressive Complex 2 (PRC2) C_LIO_LIHere we show that PRC2 inhibitors are scarcely effective as monotherapy in ACPC cells C_LIO_LIHowever the combination of PRC2 inhibitors and carboplatin is highly synergistic C_LIO_LIRNA Seq studies revealed that PRC2 inhibitors enhance carboplatin activity by modulating several key pathways, including DNA repair and apoptosis. C_LI

pharmacology and toxicology↗

bioRxiv2024

Deciphering the Transcription Factor Landscape in Neuroendocrine Prostate Cancer Progression: A Novel Approach to Understand NE Transdifferentiation

Background and ObjectiveProstate cancer (PCa) is a leading cause of cancer mortality in men, with neuroendocrine prostate cancer (NEPC) representing a particularly resistant subtype. The role of transcription factors (TFs) in the progression from prostatic adenocarcinoma (PRAD) to NEPC is poorly understood. This study aims to identify and analyze lineage-specific TF profiles in PRAD and NEPC and illustrate their dynamic shifts during NE transdifferentiation. MethodsA novel algorithmic approach was developed to evaluate the weighted expression of TFs within patient samples, enabling a nuanced understanding of TF landscapes in PCa progression and TF dynamic shifts during NE transdifferentiation. Resultsunveiled TF profiles for PRAD and NEPC, identifying 126 shared TFs, 46 adenocarcinoma-TFs, and 56 NEPC-TFs. Enrichment analysis across multiple clinical cohorts confirmed the lineage specificity and clinical relevance of these lineage-TFs signatures. Functional analysis revealed that lineage-TFs are implicated in pathways critical to cell development, differentiation, and lineage determination. Novel lineage-TF candidates were identified, offering potential targets for therapeutic intervention. Furthermore, our longitudinal study on NE transdifferentiation highlighted dynamic TF expression shifts and delineated a three-phase hypothesis for the process comprised of de-differentiation, dormancy, and re-differentiation. and proposing novel insights into the mechanisms of PCa progression. ConclusionThe lineage-specific TF profiles in PRAD and NEPC reveal a dynamic shift in the TF landscape during PCa progression, highlighting three distinct phases of NE transdifferentiation.

cancer biology↗

bioRxiv2023

Modulating membrane shape and mechanics of minimal cells by light: area increase, softening and interleaflet coupling of membrane models doped with azobenzene-lipid photoswitches

Light can effectively interrogate biological systems in a reversible and physiologically compatible manner with high spatiotemporal precision. Understanding the biophysics of photo-induced processes in bio-systems is crucial for achieving relevant clinical applications. Employing membranes doped with the photolipid azobenzene-phosphatidylcholine (azo-PC), we provide a holistic picture of light-triggered changes in membrane kinetics, morphology and material properties obtained from correlative studies on cell-sized vesicles, Langmuir monolayers, supported lipid bilayers and molecular dynamics simulations. Light-induced membrane area increase as high as [~]25% and a 10-fold decrease in the membrane bending rigidity is observed upon trans-to-cis azo-PC isomerization associated with membrane leaflet coupling and molecular curvature changes. Vesicle electrodeformation measurements and atomic force microscopy reveal that trans azo-PC bilayers are thicker than POPC bilayer but have higher specific membrane capacitance and dielectric constant suggesting an increased ability to store electric charges across the membrane. Lastly, incubating POPC vesicles with azo-PC solutions resulted in the insertion of azo-PC in the membrane enabling them to become photoresponsive. All these results demonstrate that light can be used to finely manipulate the shape, mechanical and electric properties of photolipid-doped minimal cell models and liposomal drug carriers, thus, presenting a promising therapeutic alternative for the repair of cellular disorders.

biophysics↗

bioRxiv2021

The long non-coding RNA H19 drives the proliferation of diffuse intrinsic pontine glioma with H3K27 mutation

Diffuse intrinsic pontine glioma (DIPG) is an incurable paediatric malignancy. Identifying molecular drivers of DIPG progression is of utmost importance. Long non-coding RNAs (lncRNAs) represent a large family of disease- and tissue-specific transcripts, whose functions have not been yet elucidated in DIPG. Here, we study the oncogenic role of the development-associated H19 lncRNA in DIPG. Bioinformatic analyses of clinical datasets were used to measure the expression of H19 lncRNA in paediatric high-grade gliomas (pedHGG). Expression and sub-cellular location of H19 lncRNA was validated in DIPG cell lines. Locked nucleic acid antisense oligonucleotides were designed to test the function of H19 in DIPG cells. We found that H19 expression was higher in DIPG vs normal brain tissue and other pedHGGs. H19 knockdown resulted in decreased cell proliferation and survival in DIPG cells. Mechanistically, H19 buffers let-7 microRNAs, resulting in up-regulation of oncogenic let-7 target (e.g SULF2, OSMR). H19 is the first functionally characterized lncRNA in DIPG and a promising therapeutic candidate to treat this incurable cancer.

cancer biology↗

bioRxiv2019

A pivotal role for Nrf2 in endothelial detachment- implications for endothelial erosion of stenotic plaques

Endothelial erosion of atherosclerotic plaques and resulting thrombosis causes approximately 30% of acute coronary syndromes (ACS). As changes in the haemodynamic environment strongly influence endothelial function and contribute to plaque development, we reconstructed the coronary artery geometries of plaques with thrombi overlying intact fibrous caps from 17 ACS patients and performed computational fluid dynamic analysis. The results demonstrated that erosions frequently occur within areas of stenosis exposed to elevated flow. We recapitulated this flow environment in vitro, exposing human coronary artery endothelial cells to elevated flow and modelled smoking (a risk factor for erosion) by exposure to a combination of aqueous cigarette smoke extract and TNF. This treatment induced endothelial detachment, which increased with pharmacological activation of the antioxidant system controlled by transcription factor Nrf2 (encoded by NFE2L2). The expression of Oxidative Stress Growth INhibitor genes OSGIN1 and OSGIN2 increased under these conditions and also in the aortas of mice exposed to cigarette smoke. Sustained high level expression of OSGIN1+2 resulted in cell cycle arrest, induction of senescence, loss of focal adhesions and actin stress fibres, and dysregulation of autophagy. Overexpression of either Nrf2 or OSGIN1+2 induced cell detachment, which did not depend on apoptosis, and could be partially rescued by inhibition of HSP70 using VER-155008, or AMP kinase activation using metformin. These findings demonstrate that under elevated flow, smoking-induced hyperactivation of Nrf2 can trigger endothelial cell detachment, highlighting a novel mechanism that could contribute to ACS involving endothelial erosion overlying stenotic plaques.

cell biology↗