Biology subjects

Garcia-Gilabert, L.

Publications and source records attributed to Garcia-Gilabert, L..

5 recordsLinked to original sources

bioRxiv2024

Combined inhibition of MDM2 and PARP lead to a synergistic anti-tumoral response in p53 wild-type rhabdomyosarcoma models

Targeting MDM2-p53 interaction to enhance p53 activity represents a promising antitumoral strategy for p53 wild-type pediatric tumors, including soft-tissue sarcomas. However, results from early-phase clinical trials in hematological and solid cancers have shown limited efficacy of MDM2 inhibitors, underscoring the necessity to explore more effective combinations with other agents. In this study, we provide results from a 22-drug combination screening demonstrating the therapeutic potential of combining siremadlin (MDM2 inhibitor) and olaparib (PARP inhibitor) for treating p53 wild-type rhabdomyosarcoma (p53 WT RMS). Cell survival, cell death, and apoptosis analysis revealed synergistic effects of combining siremadlin plus olaparib in vitro. The combination of both drugs led to a significant increase in p53 activity, as evidenced by p53 accumulation and K382 acetylation, along with an increased expression of bona fide p53 targets. Furthermore, treatment with both drugs resulted in significant reduction of tumor growth and increased mice overall survival when compared to single treatments and control in cell line-derived orthotopic xenograft models. Overall, our study demonstrates, for the first time, the synergistic effect of combining siremadlin plus olaparib in inhibiting p53 WT RMS tumor growth in vitro and in vivo. Our findings support the potential to study the combination of both drugs in clinical trials and warrants further investigation in other tumors with similar molecular features.

cancer biology↗

bioRxiv2024

Differential contribution of direct and indirect pathways from dorsolateral and dorsomedial striatum to motor symptoms in Huntington's disease mice

The alterations in the basal ganglia circuitry associated with motor symptoms in Huntingtons Disease (HD) have been extensively investigated. Yet, the specific contribution of the direct and indirect striatal output pathways from the dorsolateral (DLS) and dorsomedial striatum (DMS) to the motor dysfunction is still not fully understood. Here, using the symptomatic R6/1 male mouse model of HD, strong functional connectivity alterations between DMS and DLS regions with the rest of brain were observed by fMRI, particularly pronounced in the DLS. Then, we systematically evaluated how the selective optogenetic stimulation of the direct and indirect pathways from DLS and DMS influences locomotion, exploratory behavior, and motor learning. In wild type (WT) mice, optogenetic stimulation of the direct pathway from DLS and the indirect pathway from DMS elicited subtle locomotor enhancements, while exploratory behavior remained unaltered. Additionally, stimulation of the indirect pathway from DLS improved the performance in the accelerated rotarod task. In contrast, in HD mice, optogenetic stimulation of the distinct striatal pathways did not modulate these behaviors. Overall, this study points to deficits in the integration of neuronal activity in HD mice, while it contributes to deeper understanding of the complexity of motor control by the diverse striatal subcircuits.

neuroscience↗

bioRxiv2023

TRIB3 silencing promotes the downregulation of Akt pathway and PAX3-FOXO1 in high-risk rhabdomyosarcoma

BackgroundRhabdomyosarcoma (RMS), such as other childhood tumors, has witnessed treatment advancements in recent years. However, high-risk patients continue to face poor survival rates, often attributed to the presence of the PAX3/7-FOXO1 fusion proteins, which has been associated with metastasis and treatment resistance. Despite efforts to directly target these chimeric proteins, clinical success remains elusive. In this study, the main aim was to address this challenge by investigating regulators of FOXO1. Specifically, we focused on TRIB3, a potential regulator of the fusion protein in RMS. MethodsTRIB3 expression was examined through the analysis of patient datasets, including gene expression profiling and gene set enrichment analyses. In cell lines, the DepMap dataset for RMS was utilized alongside Western blot analysis to assess TRIB3 expression. The functional significance of TRIB3 in RMS was assessed through constitutive and inducible shRNA-mediated knockdowns. Subsequent in vitro and in vivo analyses, including orthotopic tumor models in immune-compromised mice, were conducted to delineate the role and underlying molecular mechanisms exerted by TRIB3 in RMS ResultsOur findings revealed a prominent TRIB3 expression in RMS tumors, highlighting its correlation with several clinical features. By conducting TRIB3 genetic inhibition experiments, we observed an impairment on cell proliferation. Notably, the knockdown of TRIB3 led to a decrease in PAX3-FOXO1 and its target genes at protein level, accompanied by a reduction in the activity of the Akt signaling pathway. Furthermore, TRIB3 influenced posttranslational modifications, such as phosphorylation together with proteasomal degradation of PAX3-FOXO1 protein. Additionally, inducible silencing of TRIB3 significantly delayed tumor growth and improved overall survival in vivo. ConclusionsBased on our comprehensive analysis, we propose that TRIB3 holds therapeutic potential for treating the most aggressive subtype of RMS. The findings herein reported contribute to our understanding of the underlying molecular mechanisms driving RMS progression and provide novel insights into the potential use of TRIB3 as a therapeutic intervention for high-risk RMS patients.

cancer biology↗

bioRxiv2022

Analysis of cancer genomic amplifications identifies druggable collateral dependencies within the amplicon

The identification of novel therapeutic targets for specific cancer molecular subtypes is crucial for the development of precision oncology. In the last years, CRISPR/Cas9 screens have accelerated the discovery and validation of new targets associated with different tumor types, mutations or fusions. However, there are still many cancer vulnerabilities associated with specific molecular features that remain to be explored. Here we used data from CRISPR/Cas9 screens in 954 cancer cell lines to identify gene dependencies associated with 16 common cancer genomic amplifications. We found that high-copy number genomic amplifications generate multiple collateral dependencies within the amplified region in 94% of cases. Further, to prioritize candidate targets for each chromosomal region amplified, we integrated gene dependency parameters with both druggability data and subcellular location. Finally, analysis of the relationship between gene expression and gene dependency leads to the identification of genes, the expression of which may constitute predictive biomarkers of dependency.

cancer biology↗

bioRxiv2022

Altered M2 Cortex - Superior Colliculus visual perception circuit in Huntington's Disease

The premotor cortical area -M2 cortex in rodents- connection to the striatum is involved in movement and prominently affected in Huntingtons Disease (HD). M2 cortex also projects to the superior colliculus (SC), implicated in oculomotor functions (i.e. saccades) and visual perception. Here, we investigated the contribution of M2 cortex - SC circuit to HD physiopathology in male mice. Using fMRI, we observed that M2 cortex functional connectivity with the SC was the most prominently affected circuit in the symptomatic R6/1 HD mouse model. Structural alterations were also detected by tractography and viral tracing. HD mice showed decreased defensive behavioral responses towards an unexpected visual stimuli, such as a moving robo-beetle, and decreased locomotion upon unexpected flash of light. Additionally, optogenetic M2 cortex - SC stimulation promoted avoidance responses towards the robo-beetle in WT, but not HD mice. Though, DWI measurements in vivo and ex vivo electrophysiological responses to optogenetic and electrical stimuli in the SC suggested preserved brain structure. Finally, GCamp6f fluorescence recordings with fiber photometry indicated that aberrant M2 cortex engagement might be the underlying mechanism of visual perception alterations in HD. Collectively, our findings point to a key role of M2 cortex - SC circuit alterations in HD pathophysiology.

neuroscience↗