Biology subjects

Ferrer, I.

Publications and source records attributed to Ferrer, I..

23 records · Page 2Linked to original sources

bioRxiv2022

Farnesyltransferase inhibition overcomes the adaptive resistance to osimertinib in EGFR-mutant NSCLC

Drug-tolerant "dormant" cells (DTC) have emerged as one of the major non-genetic mechanisms driving resistance to targeted therapy in lung cancer, although the sequence of events leading to entry and exit from dormancy remain poorly described. Here, we performed real-time monitoring of the cell cycle dynamics during the adaptive response to Epidermal Growth Factor Receptor tyrosine kinase inhibitors (EGFR-TKi) in a panel of EGFR-mutated lung cancer cell lines. We identified a rare population of S/G2 cycling cells (referred to as early escapers) that emerged in the first hours of treatment amongst stably arrested and progressively dying G1 cells. We determined that early escapers evolved from a non-proliferative differentiated alveolar type 1 (AT1) phenotype which was invariably associated with cytoskeletal remodeling through Rho/ROCK pathway activation. Using a panel of Rho-pathway inhibitors, we found that the farnesyltransferase inhibitor tipifarnib induced a complete clearance of EGFR-TKi-induced DTC thus fully preventing relapse in vitro. Using a xenograft model and a PDX model of EGFRL858R/T790M lung cancer, co-treatment with tipifarnib prevented relapse to osimertinib for up to 6 months with no evidence of toxicity. Among the farnesylated proteins regulated during osimertinib treatment, concomitant inhibition of RHOE and LaminB1 was sufficient to recapitulated FTIs effect. Osimertinib and tipifarnib co-treatment completely suppressed the emergence of AT1 phenotype, prevented mitosis of S/G2-treated cells and increased the apoptotic response through activation of ATF4-CHOP-dependent Integrated Stress Response (ISR) pathway. Our data strongly support the use of tipifarnib in combination with osimertinib in patients to effectively and durably prevent relapse.

cancer biology↗

bioRxiv2021

Involvement of mechanical cues in the migration of Cajal-Retzius cells in the marginal zone during neocortical development

Emerging evidence points to coordinated action of chemical and mechanical cues during brain development. At early stages of neocortical development, angiogenic factors and chemokines such as CXCL12, ephrins, and semaphorins assume crucial roles in orchestrating neuronal migration and axon elongation of postmitotic neurons. Here we explore the intrinsic mechanical properties of the developing marginal zone of the pallium in the migratory pathways and brain distribution of the pioneer Cajal-Retzius cells. These pioneer neurons are generated in several proliferative regions in the developing brain (e.g., the cortical hem and the pallial subpallial boundary) and migrate tangentially in the preplate/marginal zone covering the upper portion of the neocortex. These cells play crucial roles in correct neocortical layer formation by secreting several molecules such as Reelin. Our results indicate that the motogenic properties of Cajal-Retzius cells and their perinatal distribution in the marginal zone are also modulated by both chemical and mechanical factors, by the specific mechanical properties of Cajal-Retzius cells, and by the differential stiffness of the migratory routes. Indeed, cells originating in the cortical hem display higher migratory capacities than those generated in the pallial subpallial boundary which may be involved in the differential distribution of these cells in the dorsal-lateral axis in the developing marginal zone.

neuroscience↗

bioRxiv2021

Behavioral deficits, learning impairment, and enhanced hippocampal excitability in co-isogenic PrnpZH3/ZH3 mice

BackgroundThe cellular prion protein (PrPC) has been associated with numerous cellular processes, such as cell differentiation and neurotransmission. Moreover, it was recently demonstrated that some functions were misattributed to PrPC since results were obtained from mouse models with genetic artifacts. Here we elucidate the role of PrPC in the hippocampal circuitry and its related functions, like learning and memory, using the new strictly co-isogenic Prnp0/0 mouse (PrnpZH3/ZH3). Behavioral and operant conditioning tests were performed to evaluate memory and learning capabilities. In vivo electrophysiological recordings were carried out at CA3-CA1 synapses in living behaving mice, and spontaneous neuronal firing and network formation were monitored in primary neuronal cultures of PrnpZH3/ZH3 vs. wild-type mice. ResultsResults showed decreased motility, impaired operant conditioning learning, and anxiety-related behavior in PrnpZH3/ZH3 animals. PrPC absence enhanced susceptibility to high-intensity stimulations and kainate-induced seizures. However, long-term potentiation (LTP) was not enhanced in the PrnpZH3/ZH3 hippocampus. In addition, we observed a delay in neuronal maturation and network formation in PrnpZH3/ZH3 cultures. ConclusionIn conclusion, PrPC mediates synaptic function and protects the synapse from excitotoxic insults. Its deletion might evoke a susceptible epileptogenic brain that would fail to perform highly cognitive-demanding tasks such as associative learning and anxiety-like behaviors.

neuroscience↗

bioRxiv2020

CALCIUM-BINDING PROTEINS ARE ALTERED IN THE CEREBELLUM IN SCHIZOPHRENIA

Alterations in the cortico-cerebellar-thalamic-cortical circuit might underlie the diversity of symptoms in schizophrenia. However, molecular changes in cerebellar neuronal circuits, part of this network, have not yet been fully determined. Using LC-MS/MS, we screened altered candidates in pooled grey matter of cerebellum from schizophrenia subjects who committed suicide (n=4) and healthy individuals (n=4). Further validation by immunoblotting of three selected candidates was performed in two cohorts comprising schizophrenia (n=20), non-schizophrenia suicide (n=6) and healthy controls (n=21). We found 99 significantly altered proteins, 31 of them previously reported in other brain areas by proteomic studies. Transport function was the most enriched category, while cell communication was the most prevalent function. For validation, we selected the vacuolar proton pump subunit 1 (VPP1), from transport, and two EF-hand calcium-binding proteins, calmodulin and parvalbumin from cell communication. All candidates showed significant changes in schizophrenia (n=7) compared to controls (n=7). VPP1 was altered in the non-schizophrenia suicide group and increased levels of parvalbumin were linked to antipsychotics. Further validation in an independent cohort of non-suicidal chronic schizophrenia subjects (n=13) and non-psychiatric controls (n=14) showed that parvalbumin was increased while calmodulin was decrease in schizophrenia. Our findings provide evidence of an dysregulation of calcium-binding proteins in the cerebellum in schizophrenia, suggesting an impact on normal calcium-dependent synaptic functioning of cerebellar circuits. Our study also links VPP1 to suicide behaviours, suggesting a possible impairment in vesicle neurotransmitter refilling and release in these phenotypes.

neuroscience↗

bioRxiv2019

Nuclear lipidome is altered in amyotrophic lateral sclerosis: a preliminary study

In this pilot study, we show that nuclei in spinal cord from ALS patients exhibit a differential lipidomic signature. Among the differential lipid species we could annotate 41 potential identities. These comprise membrane-bound lipids such as phosphatidylethanolamines-including plasmalogens- and phosphatidylcholines but also other lipid classes such as glycosphingolipids, diacylglycerols, and triacylglycerides (potentially present as nuclear lipid droplets). These results were orthogonally validated by showing loss of alkyldihydroxyacetonephosphate synthase (AGPS), a key peroxisomal enzyme in plasmalogen synthesis, both in ALS necropsy samples, in human motor neurons derived from iPSC from ALS patients and in hSOD-G93A transgenic mice. Further, diacylglycerol content changes were associated to ALS-linked variations in related-enzymes, such as phospholipase C {beta}I (PLC{beta}I), the source of nuclear diacylglycerol, and protein kinase C{beta}II (PKC{beta}II), whose function partially depends on nuclei concentration of diacylglycerol. These results point out for not only a role of nuclear membrane lipids but also to lipids present in the nucleoplasm, suggesting an undisclosed role for this part of the subcellular lipidome in ALS pathophysiology.

neuroscience↗