Biology subjects

Blanco, I.

Publications and source records attributed to Blanco, I..

At least 19 recordsLinked to original sources

bioRxiv2026

Identification of Malignant Peripheral Nerve Sheath Tumor subtypes with distinct genomic identities

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue sarcomas arising sporadically or in people with neurofibromatosis type 1 (NF1). Their marked heterogeneity challenges diagnosis and has hampered an integrative view of MPNST molecular pathogenesis. Here, a thorough whole-genome and transcriptome analysis of MPNSTs and the re-analysis of a large independent cohort allowed us to identify three molecular subtypes of MPNSTs (G1-G3) with distinct genomic identities and clinicopathological features. Furthermore, it provided a simple and unifying model of MPNST development, defining a distinct progression path for each group. This work uncovers new genomic aspects of MPNSTs, including the identification of recurrent copy-neutral loss of heterozygosity regions, distinct copy-number profiles among G1-G3, and CDKN2A-inactivating translocations in pre-malignant lesions (ANNUBPs). Altogether, these analyses overcome the dominant influence of PRC2 status in MPNST classification and provide a framework for their differential diagnosis and potential precision oncology treatment. SIGNIFICANCEMPNST is a highly heterogeneous soft-tissue sarcoma with difficult clinical management and no effective systemic therapies. This work defines three molecular subtypes of MPNSTs with distinct development paths and histological and clinical characteristics with potential impact on translational studies and subtype-tailored treatments.

cancer biology↗

bioRxiv2025

The role of MICOS in modulating mitochondrial dynamics and structural changes in vulnerable regions of Alzheimer's Disease

Mitochondrial contact site and cristae organizing system (MICOS) complexes are critical for maintaining the mitochondrial architecture, cristae integrity, and organelle communication in neurons. MICOS disruption has been implicated in neurodegenerative disorders, including Alzheimers disease (AD), yet the spatiotemporal dynamics of MICOS-associated neuronal alterations during aging remain unclear. Using three-dimensional reconstructions of hypothalamic and cortical neurons, we observed age-dependent fragmentation of mitochondrial cristae, reduced intermitochondrial connectivity, and compartment-specific changes in mitochondrial size and morphology. Notably, these structural deficits were most pronounced in neurons vulnerable to AD-related pathology, suggesting a mechanistic link between MICOS disruption and the early mitochondrial dysfunction observed in patients with AD. Our findings indicate that the loss of MICOS integrity is a progressive feature of neuronal aging, contributing to impaired bioenergetics and reduced resilience to metabolic stress and potentially facilitating neurodegenerative processes. MICOS disruption reduced neuronal firing and synaptic responsiveness, with miclxin treatment decreasing mitochondrial connectivity and inducing cristae disorganization. These changes link MICOS structural deficits directly to impaired neuronal excitability, highlighting vulnerability to AD-related neurodegeneration. These results underscore the importance of MICOS as a critical determinant of neuronal mitochondrial health and as a potential target for interventions aimed at mitigating AD-related mitochondrial dysfunction.

neuroscience↗

bioRxiv2025

Varied monoamine reuptake inhibitors reduce parvalbumin expression; implications for pyramidal cell disinhibition and enhanced neuroplasticity

First-line antidepressants are effective in a significant percent of individuals but a full understanding of how these therapeutics target specific endpoints is lacking. Prior work has shown that depression is associated with hippocampal atrophy and that antidepressants can increase neurotrophin levels to increase hippocampal neurogenesis as well as hippocampal pyramidal cell (PC) spine density and arbor. These effects likely contribute to amelioration of symptoms. A less well-explored possibility is that antidepressants concomitantly disinhibit hippocampal PC activity, which could also facilitate increased PC arbor, spinogenesis and/or activity. In accordance, previous studies have shown antidepressants can attenuate stress-induced upregulation of perineuronal nets (PNNs). PNNs are predominantly localized to parvalbumin (PV) expressing GABAergic interneurons and increase PV expression and neuronal activity. Though specific antidepressants have been explored for effects on regional PNN expression, the question of whether hippocampal PNN/ECM remodeling is a shared feature of varied antidepressant drugs and more importantly, of whether it is associated with significant hippocampal PV inhibition, has not been well-addressed. Herein we examine three monoamine reuptake inhibitors, fluoxetine, venlafaxine and viloxazine, in animal models for effects on PNN remodeling and PV expression, a proxy for PV activity. We observe shared effects of these therapeutics including the ability to increase PNN degrading effectors that can downregulate PV activity. Consistent with this, we observe shared effects of these drugs in terms of their ability to significantly reduce PV levels. These findings highlight the possibility that ECM remodeling and associated hippocampal PC disinhibition represent a shared feature of varied antidepressant medications.

neuroscience↗

bioRxiv2025

NF2 lacking exon 11 isoform induced by antisense gene therapy is able to recover partially merlin deficiency on NF2-related Schwannomatosis iPSC-derived spheroid model

NF2-related Schwannomatosis (NF2-SWN) is an inherited autosomal dominant disorder resulting from loss-of-function mutations in the NF2 gene, for which no effective treatment is currently available. Furthermore, truncating variants in NF2 are associated with the severest phenotype compared to in-frame or missense variants. Previously, a shorter NF2 isoform with exon 11 skipped (merlin_e-11), induced through antisense morpholino oligomers (PMOs), was able to partially rescue the deleterious effect of nonsense variants located at that exon in patients primary fibroblast. To test the potential of this approach into Schwann cells, those responsible of NF2-SWN tumours, we developed an iPSC-based model carrying heterozygous and homozygous truncating variants on exon 11 of the NF2 gene and differentiated them to Schwann cells forming spheroids. After 3 days of treatment, merlin_e-11 expression was induced in NF2-deficient cell lines. Furthermore, key pathways associated with NF2-deficiency in schwannomas, such as PI3K/Akt/mTORC and YAP levels, were recovered without signs of toxicity. These results confirm that the PMO treatment induces effective skipping of exon 11 in Schwann cell spheroids, generating an hypomorphic merlin_e-11 that has the capacity to partially rescue merlin-deficiency in NF2-SWN spheroid cell model and it being a potential treatment of patients harbouring truncating variants located in exon 11.

genetics↗

bioRxiv2025

Increased levels of HAPLN2, which anchors dense extracellular matrix, in the hippocampus of APOE4 targeted replacement mice

Hyaluronan and proteoglycan link protein 2 (HAPLN2) / Brain link protein-1 (Bral1) is important for the binding of chondroitin sulfate proteoglycans (CSPGs) to hyaluronan and thus for the formation of specific types of brain extracellular matrix (ECM). It is also significantly increased with aging. Moreover, machine learning has identified it as a brain-derived protein most predictive of Alzheimers disease (AD). HAPLN2 binds to CSPGs that may sequester aggregation-prone proteins and also restrict neuronal plasticity. Because the apolipoprotein 4 (APOE4) allele increases AD risk, in the present study we have examined hippocampal lysates from APOE3 and APOE4 targeted replacement (TR) mice using unbiased proteomics, Western blot and hippocampal immunostaining. With proteomics, we observe that HAPLN2 is among the most significantly upregulated proteins in APOE4 mice. Prior work suggests HAPLN2 is particularly important to the assembly of perinodal matrix, and herein we show that it also co-localizes with Wisteria floribunda agglutinin (WFA) positive perineuronal nets (PNNs). PNNs represent a dense form of ECM that can increase GABAergic neurotransmission to alter overall excitatory/inhibitory (E/I) balance and neuronal oscillations important to mood and memory. Proteomics also detected elevated levels of high temperature requirement peptidase-1 (HTRA1), which accumulates in cerebral blood vessels harboring amyloid, in APOE4 mice. In Western blot studies, lysates from APOE4 mice also showed significantly reduced levels chondroitin-6 sulfated proteoglycans, which makes PNNs more susceptible to proteolysis and less inhibitory. In addition, immunostaining studies showed that levels of the PNN component aggrecan were increased in the hippocampus of APOE4 animals. Overall, these findings contribute to an emerging body of literature suggesting that brain extracellular matrix may be altered with aging and other risk factors for AD, and suggest that future studies should assess PNNs, peri-nodal structure and axonal conduction in the background of APOE4.

neuroscience↗

bioRxiv2025

MMP-2/9 inhibition modulates sharp wave abundance, inhibitory proteoglycan sulfation, and fear memory in juvenile zebrafish: relevance to affective disorders

Sharp wave ripple (SWR) events, present in diverse species, spontaneously occur in the hippocampus during quiescent restfulness and slow-wave sleep. SWRs comprise a negative deflection, the sharp wave (SW) event with an often-superimposed ripple (R) and are the neural correlates of memory consolidation and recall. The Anterodorsolateral lobe (ADL) (zebrafish hippocampal homologue) exhibits SW and SWR events, and since SWs initiate SWRs, their abundance typically shows the same directionality. In previous work, we observed matrix metalloproteinase-9 (MMP-9)-dependent effects on depression-relevant behaviors, perineuronal net (PNN) levels, and SWR abundance in the adult rodent hippocampus. Here, we investigate MMP-2/9-dependent effects on biochemical, behavioral, and neurophysiological endpoints in juvenile zebrafish and zebrafish at the transition from the late juvenile period to early adulthood. With MMP-2/9 inhibition, juvenile zebrafish showed reduced SW amplitude and abundance together with increased fear memory retention and reduced sociability. Juvenile zebrafish also showed an increased percentage of longer-duration SW events. Except for a reduction in SW amplitude, these changes were not observed at the transition from late juvenile to early adulthood. These changes were accompanied by increased levels of chondroitin sulfate (CS) proteoglycan 4-O-sulfation, which modulates PNNs and excitatory-to-inhibitory (E/I) balance. Discontinuation of MMP-2/9 inhibition in juvenile zebrafish normalized deficits in ADL SW abundance and sociability. Together, these findings show that MMP-2/9 significantly influences E/I balance and learning and memory during the highly plastic juvenile period in zebrafish. Findings also have relevance to an emerging appreciation of PNN changes that may contribute to altered neuronal oscillations and mood or cognition.

neuroscience↗

bioRxiv2023

Post-ischemic ubiquitination at the postsynaptic density reversibly influences the activity of ischemia-relevant kinases

Ubiquitin modifications alter protein function and stability, thereby regulating cell homeostasis and viability, particularly under stress. Ischemic stroke induces protein ubiquitination at the ischemic periphery, wherein cells remain viable, however the identity of ubiquitinated proteins is unknown. Here, we employed a proteomics approach to identify these proteins in mice undergoing ischemic stroke. The data are available in a searchable web interface (https://hochrainerlab.shinyapps.io/StrokeUbiOmics/). We detected increased ubiquitination of 198 proteins, many of which localize to the postsynaptic density (PSD) of glutamatergic neurons. Among these were proteins essential for maintaining PSD architecture, such as PSD95, as well as NMDA and AMPA receptor subunits. The largest enzymatic group at the PSD with elevated post-ischemic ubiquitination were kinases, such as CaMKII, PKC, Cdk5, and Pyk2, whose aberrant activities are well-known to contribute to post-ischemic neuronal death. Concurrent phospho-proteomics revealed altered PSD-associated phosphorylation patterns, indicative of modified kinase activities following stroke. PSD-located CaMKII, PKC, and Cdk5 activities were decreased while Pyk2 activity was increased after stroke. Removal of ubiquitin restored kinase activities to pre-stroke levels, identifying ubiquitination as the responsible molecular mechanism for post-ischemic kinase regulation. These findings unveil a previously unrecognized role of ubiquitination in the regulation of essential kinases involved in ischemic injury.

neuroscience↗

bioRxiv2023

Sharp wave ripple coupling in zebrafish hippocampus and basolateral amygdala

The mammalian hippocampus exhibits sharp wave events (1-30 Hz) with an often-present superimposed fast ripple oscillation (120-200 Hz) forming a sharp wave ripple (SWR) complex. During slow wave sleep or consummatory behaviors, SWRs result from the sequential spiking of hippocampal cell assemblies initially activated during imagined or learned experiences. SWRs occur in tandem with cortical/subcortical assemblies critical to the long-term storage of specific memory types. Leveraging juvenile zebrafish, we show that SWR events in their hippocampal homologue, the anterodorsolateral lobe (ADL), in ex vivo whole-brains are locally generated and maintained. SWR events were also recorded in the basolateral amygdala (BLA). Concomitant single cell calcium imaging and local field potential (LFP) recordings showed that BLA SWs couple to ADL SWs. Calcium imaging recordings of whole-brains demonstrated that ADL and BLA SWRs are endogenously and spontaneously silenced by the activation of a more caudal population of putative cholinergic cells. Electrical stimulation of this caudal region silenced ADL SWs. Our results suggest that the SWR-generating circuit is evolutionarily conserved through shared acetylcholine modulating mechanisms. These findings further our understanding of neuronal population dynamics in the zebrafish brain and highlights their advantage for simultaneously recording SW/SWRs and single cell activity in diverse brain regions.

neuroscience↗

bioRxiv2022

Unbalancing cAMP and Ras/MAPK pathways as a therapeutic strategy for cutaneous neurofibromas

Cutaneous neurofibromas (cNFs) are benign Schwann cell (SC) tumors arising from subepidermal glia. Neurofibromatosis Type 1 (NF1) individuals may develop thousands of cNFs, greatly affecting their quality of life. cNF growth is governed by the proliferation of NF1(-/-) SCs, highly influenced by the interaction with a NF1(+/-) microenvironment, consisting of fibroblasts (FBs), immune cells, etc. To decompose crosstalk between SCs and the microenvironment we used single cultures and co-cultures of cNF-derived SCs and FBs and identified an expression signature specific to SC-FB interaction. This signature was enriched in genes involved in immune cell migration, that were functionally validated by secretion analysis of SC-FB co-cultures, suggesting a role of SC-FB crosstalk in immune cell recruitment. The signature also captured components of different developmental signaling pathways, among them, the cAMP elevator G protein-coupled receptor 68 (GPR68). Activation of Gpr68 by Ogerin reduced the viability and proliferation of cNF-derived SCs and SC-FB co-cultures. Moreover, Ogerin in combination with the MEKi Selumetinib induced loss of viability, SC differentiation, and death. These results were corroborated using an iPSC-derived 3D neurofibromasphere model. The unbalancing of the Ras and cAMP pathways by combining a MEKi and a cAMP elevator arises as a potential treatment for cNFs.

cancer biology↗

bioRxiv2022

Merlin-deficient iPSCs show altered pluripotency and constitute a potential in vitro model for NF2-related schwannomas

NF2-related schwannomatosis is an autosomal dominant syndrome that predisposes to the development of benign tumors of the nervous system. Schwannomas, particularly bilateral vestibular schwannomas (VS), are the most characteristic features of the disease. These tumors are caused by the bi-allelic inactivation of the NF2 gene in a cell of the Schwann cell lineage. Our current understanding of the molecular pathogenesis of the NF2 gene, as well as the development of new effective therapies is hampered by the absence of human non-perishable cell-based bearing distinct NF2 pathogenic variants. With this aim, we generated and characterized three isogenic paired induced pluripotent stem cell (iPSC) lines with single or bi-allelic inactivation of NF2 by combining the direct reprogramming of VS cells with the use of CRISPR/Cas9 editing. Our results show a critical function of NF2 for the maintenance of a stable pluripotent state. However, we were able to nudge them towards the Neural Crest-Schwann Cell (NC-SC) axis by applying a 3D Schwann cell differentiation protocol. NF2(+/-) and NF2(-/-) spheroids homogeneously expressed classical markers of the NC-SC lineage. In addition, NF2(-/-) SC-like spheroids showed dysregulation of multiple signaling pathways already described for merlin-deficient SC, and altered in human schwannomas. Therefore, NF2(+/-) and NF2(-/-) SC-like spheroids can represent a bona fide human in vitro cellular model to study the role of NF2 pathogenesis.

cell biology↗

bioRxiv2022

A detailed landscape of genomic alterations in malignant peripheral nerve sheath tumor cell lines challenges the current MPNST diagnosis

BackgroundMalignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that arise from the peripheral nervous system. Half of the tumors develop in the context of the genetic disease Neurofibromatosis type 1 (NF1) and the rest are sporadic sarcomas. MPNSTs have a dismal prognosis due to their aggressiveness and tendency to metastasize, and new treatment options are needed. The diagnosis of MPNSTs can be challenging, especially outside of the NF1 context since specific histological criteria have not been completely established. Genomic analysis may both facilitate differential diagnoses and suggest precision medicine strategies. MethodsWe generated a complete genomic resource of a set of widely used human NF1-related and sporadic MPNST cell lines by applying ploidy analysis, whole genome and whole exome sequencing and SNP-array analysis, complemented by methylome-based classification and immunofluorescence of cell identity markers (SOX9, SOX10, S100B). ResultsNF1 MPNST cell lines faithfully recapitulated the genomic copy number profile of primary MPNSTs. Structural variants were key players in the complete inactivation of most recurrently altered tumor suppressor genes (TSGs) (NF1, CDKN2A, SUZ12/EED), while small variants played a minor role in the NF1 context, both concerning TSG inactivation and due to the absence of gain-of-function mutations. In clear contrast, the sporadic cell lines (STS-26T, HS-Sch-2, HS-PSS) did not recapitulate the copy number profile of primary MPNSTs. They carried different TSG inactivation and exhibited gain-of-function mutations by predicted kinase activation or generation of fusion genes. Mutational frequencies and signatures emerged as promising informative tools for aiding in MPNST differential diagnosis. Due to the multiple genomic differences exhibited, we complemented their characterization using a methylome-based classifier. All NF1-related cell lines were assigned within the MPNST group, while sporadic cell lines clustered either with melanomas or with an uncertain MPNST-like sarcoma group. The staining of cell identity markers reinforced the idea of a potential misdiagnose of the MPNSTs used to derive the sporadic cell lines analyzed. ConclusionsDeep genomic analysis, together with methylome-based sarcoma classification and cell identity marker analysis, challenged the MPNST identity of sporadic cell lines. Results presented here open an opportunity to revise MPNST differential diagnosis and classification.

genomics↗

bioRxiv2022

Antisense oligonucleotides targeting exon 11 are able to partially rescue the Neurofibromatosis Type 2 phenotype in vitro

Neurofibromatosis type 2 (NF2) is an autosomal dominant condition caused by loss of function variants in the NF2 gene, which codes for the protein Merlin, and characterized by the development of multiple tumours of the nervous system. The clinical presentation of the disease is variable and related to the type of the inherited germline variant. Here, we tested if PMOs could be used to correct the splice signalling caused by variants at +/-13 within the intron-exon boundary region. Here we show that the PMOs designed for these variants do not constitute a therapeutic approach. Furthermore, we evaluated the use of phosphorodiamidate morpholino oligomers (PMOs) to reduce the severity of the effects of NF2 truncating variants with the aim of generating milder hypomorphic isoforms in vitro through the induction of the in-frame deletion of the exon-carrying variant. We were able to specifically induce the skipping of exons 4, 8 and 11 maintaining the NF2 gene reading frame at cDNA level. Only the skipping of exon 11 produced a hypomorphic Merlin (Merlin-e11), able to partially rescue the observed phenotype in primary fibroblast cultures from NF2 patients, being encouraging for the treatment of patients harbouring truncating variants located in exon 11.

genetics↗

bioRxiv2021

SARS-CoV-2 B.1.351 (beta) variant shows enhanced infectivity in K18-hACE2 transgenic mice and expanded tropism to wildtype mice compared to B.1 variant

SARS-CoV-2 variants display enhanced transmissibility and/or immune evasion and can be generated in humans or animals, like minks, thus generating new reservoirs. The continuous surveillance of animal susceptibility to new variants is necessary to predict pandemic evolution. In this study we demonstrate that, compared to the B.1 SARS-CoV-2 variant, K18-hACE2 transgenic mice challenged with the B.1.351 variant displayed a faster progression of infection. Furthermore, we also report that B.1.351 can establish infection in wildtype mice, while B.1 cannot. B.1.351-challenged wildtype mice showed a milder infection than transgenic mice, confirmed by detectable viral loads in oropharyngeal swabs and tissues, lung pathology, immunohistochemistry and serology. In silico models supported these findings by demonstrating that the Spike mutations in B.1.351 resulted in increased affinity for both human and murine ACE2 receptors. Overall, this study highlights the plasticity of SARS-CoV-2 animal susceptibility landscape, which may contribute to viral persistence and expansion.

microbiology↗

bioRxiv2021

Siglec-1 on dendritic cells mediates SARS-CoV-2 trans-infection of target cells while on macrophages triggers proinflammatory responses

COVID-19 pandemic is not yet under control by vaccination, and effective antivirals are critical for preparedness. Here we report that macrophages and dendritic cells, key antigen presenting myeloid cells (APCs), are largely resistant to SARS-CoV-2 infection. APCs effectively captured viruses within cellular compartments that lead to antigen degradation. Macrophages sense SARS-CoV-2 and released higher levels of cytokines, including those related to cytokine storm in severe COVID-19. The sialic acid-binding Ig-like lectin 1 (Siglec-1/CD169) present on APCs, which interacts with sialylated gangliosides on membranes of retroviruses or filoviruses, also binds SARS-CoV-2 via GM1. Blockage of Siglec-1 receptors by monoclonal antibodies reduces SARS-CoV-2 uptake and transfer to susceptible target cells. APCs expressing Siglec-1 and carrying SARS-CoV-2 are found in pulmonary tissues of non-human primates. Single cell analysis reveals the in vivo induction of cytokines in those macrophages. Targeting Siglec-1 could offer cross-protection against SARS-CoV-2 and other enveloped viruses that exploit APCs for viral dissemination, including those yet to come in future outbreaks.

microbiology↗

bioRxiv2021

Highly functional Cellular Immunity in SARS-CoV-2 Non-Seroconvertors is associated with immune protection

The role of T cells in the control of SARS-CoV-2 infection has been underestimated in favor of neutralizing antibodies. However, cellular immunity is essential for long-term viral control and protection from disease severity. To understand T-cell immunity in the absence of antibody generation we focused on a group of SARS-CoV-2 Non-Seroconvertors (NSC) recovered from infection. We performed an immune comparative analysis of SARS-CoV-2 infected individuals stratified by the absence or presence of seroconversion and disease severity. We report high levels of total naive and low effector CD8+ T cells in NSC. Moreover, polyfunctional Nucleocapsid (NP)-specific CD8+ T-cell responses, as well as reduced levels of T-cell activation monitored by PD-1 and activation-induced markers, were distinctive immunological traits in NSC. Longitudinal data support the stability of the NSC phenotype over three months. Our results implicate highly functional SARS-CoV-2 Spike and NP T-cell responses with low immune activation in protection from disease severity in the absence of seroconversion. SUMMARYTo understand SARS-CoV-2 specific T-cell immunity in the absence of seroconversion, we characterized immunological features of Non-Seroconvertors recovered from infection. Highly functional specific T-cell responses and low immune activation were determinants of immune protection from severe disease.

immunology↗

bioRxiv2021

Previous SARS-CoV-2 infection increases B.1.1.7 cross-neutralization by vaccinated individuals.

To assess the potential impact of predominant circulating SARS-CoV-2 variants on neutralizing activity of infected and/or vaccinated individuals, we analyzed neutralization of pseudoviruses expressing the spike of the original Wuhan strain, the D614G and B.1.1.7 variants. Our data show that parameters of natural infection (time from infection and infecting variant) determined cross-neutralization. Importantly, upon vaccination, previously infected individuals developed equivalent B.1.1.7 and Wuhan neutralizing responses. In contrast, uninfected vaccinees showed reduced neutralization against B.1.1.7. FundingThis study was funded by Grifols, the Departament de Salut of the Generalitat de Catalunya, the Spanish Health Institute Carlos III, CERCA Programme/Generalitat de Catalunya, and the crowdfunding initiatives #joemcorono, BonPreu/Esclat and Correos.

immunology↗

bioRxiv2020

Molecular markers characterization determining cell fate specification in an adult neurogenesis model of Alzheimer's disease

Adult hippocampal neurogenesis (AHN) study is still a challenge. In addition to methodological difficulties is the controversy of results derived of human or animal system approaches. In view of the proven link between AHN and learning and memory impairment, we generated a straightforward in vitro model to recapitulate adult neurogenesis in the context of Alzheimer's disease (AD). Neural progenitor cells (NPCs) monolayer culture was differentiated for a period of 29 days and A{beta} peptide 1-42 was administered once a week. mRNA expression of NEUROD1, NCAM1, TUBB3, RBFOX3, CALB1 and GFAP genes was determined by RT-qPCR. Phenotypic changes were observed during directed differentiation. Except for GFAP and CALB1, these changes correlated with altered expression profile of all genes since 9 days. Only TUBB3 expression remained constant while NEUROD1, NCAM1 and RBFOX3 expression increased over time. Moreover, A{beta} treated NPCs showed transient decreases of mRNA expression for NCAM1, TUBB3 and RBFOX3 genes at 9 or 19 days. Our in vitro human NPCs model is framed within the multistep process of AHN in the SGZ of the DG. Remarkably, its transcriptional assessment might reflect alterations detected in AD human patients, deepening our understanding of the disorder and possibly of its pathogenesis.

neuroscience↗

bioRxiv2020

HUMAN PANCREATIC CANCER CELLS UNDERGO PROFOUND METABOLIC REPROGRAMMING TOWARDS CELLULAR STEMNESS AS ADAPTATION TO INHIBITION OF THE AKT PATHWAY

Cancer cells acquire resistance to cytotoxic therapies targeting major survival pathways by adapting their metabolism. The AKT pathway is a major regulator of human pancreatic adenocarcinoma progression. The mechanisms of adaptation to long-term silencing of AKT isoforms of pancreatic cancer cells were studied. Following silencing, cancer cells remained quiescent for long periods of time, after which they recovered proliferative capacities. Adaptation caused profound proteomic changes largely affecting mitochondrial biogenesis, energy metabolism, and acquisition of a number of distinct cancer stem cell (CSC) characteristics depending on the AKT isoform that was silenced. The adaptation to AKT1 silencing drove most de-differentiation and acquisition of stemness through C-MYC down-modulation and NANOG up-regulation, which were required for survival of adapted CSCs. The changes associated to adaptation sensitized cancer cells to inhibitors targeting regulators of oxidative respiration and mitochondrial biogenesis. In vivo pharmacological co-inhibition of AKT and mitochondrial metabolism effectively controlled pancreatic adenocarcinoma growth in pre-clinical models.

cancer biology↗