Biology subjects

Russo, S.

Publications and source records attributed to Russo, S..

48 records · Page 3Linked to original sources

bioRxiv2021

Patient-derived triple negative breast cancer organoids provide robust model systems that recapitulate tumor intrinsic characteristics

Triple negative breast cancer (TNBC) is an aggressive form of breast cancer with poor patient outcomes, and an unmet clinical need for targeted therapies and better model systems. Here, we developed and comprehensively characterized a diverse biobank of normal and breast cancer patient-derived organoids (PDOs) with a focus on TNBCs. PDOs recapitulated patient tumor intrinsic properties and a subset of PDOs can be propagated for long-term culture (LT-TNBCs). Single cell profiling of PDOs identified cell types and gene candidates affiliated with different aspects of cancer progression. The LT-TNBC organoids exhibit signatures of aggressive MYC-driven basal-like breast cancers and are largely comprised of luminal progenitor (LP)-like cells. The TNBC LP-like cells are distinct from normal LPs and exhibit hyperactivation of NOTCH and MYC signaling. Overall, our study validates TNBC PDOs as robust models for understanding breast cancer biology and progression, paving the way for personalized medicine and tailored treatment options. Statement of SignificanceA comprehensive analysis of TNBC patient-derived organoids is presented by genomic, transcriptomic, and in-vivo analyses, providing insights into cellular heterogeneity and mechanisms of tumorigenesis at the single cell level.

cancer biology↗

bioRxiv2021

A comparative study between state-of-the-art MRI deidentification and AnonyMI, a new method combining re-identification risk reduction and geometrical preservation

Deidentifying MRIs constitutes an imperative challenge, as it aims at precluding the possibility of re-identification of a research subject or patient, but at the same time it should preserve as much geometrical information as possible, in order to maximize data reusability and to facilitate interoperability. Although several deidentification methods exist, no comprehensive and comparative evaluation of deidentification performance has been carried out across them. Moreover, the possible ways these methods can compromise subsequent analysis has not been exhaustively tested. To tackle these issues, we developed AnonyMI, a novel MRI deidentification method, implemented as a user-friendly 3D Slicer plugin-in, which aims at providing a balance between identity protection and geometrical preservation. To test these features, we performed two series of analyses on which we compared AnonyMI to other two state-of-the-art methods, to evaluate, at the same time, how efficient they are at deidentifying MRIs and how much they affect subsequent analyses, with particular emphasis on source localization procedures. Our results show that all three methods significantly reduce the re-identification risk but AnonyMI provides the best geometrical conservation. Notably, it also offers several technical advantages such as a user-friendly interface, multiple input-output capabilities, the possibility of being tailored to specific needs, batch processing and efficient visualization for quality assurance.

neuroscience↗

bioRxiv2021

History of winning and hierarchy landscape influence stress susceptibility in mice

Social hierarchy formation is strongly evolutionarily conserved. Across species, rank within social hierarchy has large effects on health and behavior. To investigate the relationship between social rank and stress susceptibility, we exposed ranked male and female mice to social and non-social stressors and manipulated social hierarchy position. We found that rank predicts same sex social stress outcomes: dominance in males and females confers resilience while subordination confers susceptibility. Pre-existing rank does not predict non-social stress outcomes in females and weakly does so in males, but rank emerging under stress conditions reveals social interaction deficits in male and female subordinates. Both history of winning and rank of cage mates affect stress susceptibility in males: rising to the top rank through high mobility confers resilience and mice that lose dominance lose stress resilience, though gaining dominance over a subordinate animal does not confer resilience. Overall, we have demonstrated a relationship between social status and stress susceptibility, particularly when taking into account individual history of winning and the overall hierarchy landscape in male and female mice.

neuroscience↗

bioRxiv2021

A novel immunopeptidomic-based pipeline for the generation of personalized oncolytic cancer vaccines

Beside the isolation and identification of MHC-I restricted peptides from the surface of cancer cells, one of the challenges is eliciting an effective anti-tumor CD8+ T cell mediated response as part of therapeutic cancer vaccine. Therefore, the establishment of a solid pipeline for the downstream selection of clinically relevant peptides and the subsequent creation of therapeutic cancer vaccines are of utmost importance. Indeed, the use of peptides for eliciting specific anti-tumor adaptive immunity is hindered by two main limitations: the efficient selection of the most optimal candidate peptides and the use of a highly immunogenic platform to combine with the peptides to induce effective tumor-specific adaptive immune responses. Here, we describe for the first time a streamlined pipeline for the generation of personalized cancer vaccines starting from the isolation and selection of the most immunogenic peptide candidates expressed on the tumor cells and ending in the generation of efficient therapeutic oncolytic cancer vaccines. This immunopeptidomics-based pipeline was carefully validated in a murine colon tumor model CT26. Specifically, we used state-of-the-art immunoprecipitation and mass spectrometric methodologies to isolate >8000 peptide targets from the CT26 tumor cell line. The selection of the target candidates was then based on two separate approaches: RNAseq analysis and the HEX software. The latter is a tool previously developed by Chiaro et al. (1), able to identify tumor antigens similar to pathogen antigens, in order to exploit molecular mimicry and tumor pathogen cross-reactive T-cells in cancer vaccine development. The generated list of candidates (twenty-six in total) was further tested in a functional characterization assay using interferon-{gamma} ELISpot (Enzyme-Linked Immunospot), reducing the number of candidates to six. These peptides were then tested in our previously described oncolytic cancer vaccine platform PeptiCRAd, a vaccine platform that combines an immunogenic oncolytic adenovirus (OAd) coated with tumor antigen peptides. In our work, PeptiCRAd was successfully used for the treatment of mice bearing CT26, controlling the primary malignant lesion and most importantly a secondary, non-treated, cancer lesion. These results confirmed the feasibility of applying the described pipeline for the selection of peptide candidates and generation of therapeutic oncolytic cancer vaccine, filling a gap in the field of cancer immunotherapy, and paving the way to translate our pipeline into human therapeutic approach.

cancer biology↗

bioRxiv2021

The long non-coding RNA MaTAR20 promotes mammary tumor growth by regulating angiogenesis pathways

Long non-coding RNAs (lncRNAs) are an emerging class of regulatory molecules that have been shown to play important roles in tumorigenesis and cancer progression. Here, we studied the recently identified lncRNA Mammary Tumor Associated RNA 20 (MaTAR20) in mammary cancer progression. A CRISPR/Cas9 knockout of MaTAR20 in the metastatic 4T1 cell line led to reduced cancer cell proliferation and increased cell surface adhesion compared to control cells. Consistent with these knockout results antisense oligonucleotide (ASO) mediated knockdown of MaTAR20 resulted in reduced growth and invasion in 4T1 cells, and in primary mammary tumor organoids derived from the MMTV-PyMT mouse model of breast cancer. Injection of MaTAR20-specific ASOs subcutaneously into tumor bearing MMTV-PyMT mice resulted in smaller and highly necrotic tumors in comparison to mice injected with a scrambled control ASO. To investigate the molecular mechanism by which MaTAR20 acts to advance mammary tumor progression, we applied a combination of RNA-sequencing and RNA-pulldown coupled to DNA-sequencing. These analyses demonstrated that the nuclear retained lncRNA is associated with several essential cancer signaling pathways such as VEGF signaling. In particular, MaTAR20 directly binds to and regulates the expression of Tnfsf15. Our results indicate that MaTAR20 is an important driver of mammary tumor progression and represents a promising new therapeutic target.

cancer biology↗

bioRxiv2020

Cocaine-induced neuron subtype mitochondrial dynamics through Egr3 transcriptional regulation

Mitochondrial function is required for brain energy homeostasis and neuroadaptation. Recent studies demonstrate that cocaine affects mitochondrial dynamics and morphological characteristics within the nucleus accumbens (NAc). Further, mitochondria are differentially regulated by cocaine in dopamine receptor-1 containing medium spiny neurons (D1-MSNs) vs dopamine receptor-2 (D2)-MSNs. However, there is little understanding into cocaine-induced transcriptional mechanisms and their role in regulating mitochondrial processes. Here, we demonstrate that cocaine enhances binding of the transcription factor, early growth response factor 3 (Egr3), to nuclear genes involved in mitochondrial function and dynamics. Moreover, cocaine exposure regulates mRNA of these mitochondria-associated nuclear genes in both contingent or noncontingent cocaine administration and in both rodent models and human postmortem tissue. Interestingly, several mitochondrial nuclear genes showed distinct profiles of expression in D1-MSNs vs D2-MSNs, with cocaine exposure generally increasing mitochondrial-associated nuclear gene expression in D1-MSNs vs suppression in D2-MSNs. We further show that blunting Egr3 expression in D1-MSNs blocks cocaine-enhancement of the mitochondrial-associated transcriptional coactivator, peroxisome proliferator-activated receptor gamma coactivator (PGC1), and the mitochondrial fission molecule, dynamin related protein 1 (Drp1). Finally, reduction of D1-MSN Egr3 expression attenuates cocaine-induced enhancement of small-sized mitochondria, causally demonstrating that Egr3 regulates mitochondrial morphological adaptations. Collectively, these studies demonstrate cocaine exposure impacts mitochondrial dynamics and morphology by Egr3 transcriptional regulation of mitochondria-related nuclear gene transcripts; indicating roles for these molecular mechanisms in neuronal function and plasticity occurring with cocaine exposure.

neuroscience↗

bioRxiv2020

Simultaneous human intracerebral stimulation and HD-EEG: ground-truth for source localization methods

Precisely localizing the sources of brain activity as recorded by EEG is a fundamental procedure and a major challenge for both research and clinical practice. Even though many methods and algorithms have been proposed, their relative advantages and limitations are still not well established. Moreover, these methods involve tuning multiple parameters, for which no principled way of selection exists yet. These uncertainties are emphasized due to the lack of ground-truth for their validation and testing. Here we provide the first open dataset that comprises EEG recorded electrical activity originating from precisely known locations inside the brain of living humans. High-density EEG was recorded as single-pulse biphasic currents were delivered at intensities ranging from 0.1 to 5 mA through stereotactically implanted electrodes in diverse brain regions during pre-surgical evaluation of patients with drug-resistant epilepsy. The uses of this dataset range from the estimation of in vivo tissue conductivity to the development, validation and testing of forward and inverse solution methods.

neuroscience↗

bioRxiv2020

MaTAR25 LncRNA Regulates the Tensin1 Gene to Impact Breast Cancer Progression

Misregulation of long non-coding RNA genes has been linked to a wide variety of cancer types. Here we report on Mammary Tumor Associated RNA 25 (MaTAR25), a nuclear enriched and chromatin associated lncRNA that plays a role in mammary tumor cell proliferation, migration, and invasion, both in vitro and in vivo. MaTAR25 functions by interacting with purine rich element binding protein B (PURB), and associating with a major downstream target gene Tensin 1 (Tns1) to regulate its expression in trans. Knockout of MaTAR25 results in down-regulation of Tns1 leading to a reorganization of the actin cytoskeleton, and a reduction of focal adhesions and microvilli. The human ortholog of MaTAR25, LINC01271, is upregulated with human breast cancer stage and metastasis. SIGNIFICANCELncRNAs have great potential to reveal new regulatory mechanisms of function as well as having exciting therapeutic capacity given their ease of being targeted by nucleic acid drugs. Our study of MaTAR25, and its human ortholog LINC01271, reveal an unexpected function of this lncRNA in breast cancer progression by regulating Tns1 gene expression, whose protein product is a critical component of focal adhesions linking signaling between the extracellular matrix and the actin cytoskeleton. We identified LINC01271 as the human ortholog of MaTAR25, and importantly, increased expression of LINC01271 is associated with poor patient prognosis and cancer metastasis. Our findings demonstrate that LINC01271 represents an exciting therapeutic target to alter breast cancer progression.

cancer biology↗

bioRxiv2019

Orexin signaling in GABAergic lateral habenula neurons modulates aggressive behavior

Heightened aggression is characteristic of multiple neuropsychiatric disorders and can have a wide variety of negative effects on patients, their families, and the public. Recent studies in humans and animals have implicated brain reward circuits in aggression and suggest that, in subsets of aggressive individuals, repeated domination of subordinate social targets is reinforcing. Here, we show that orexin neurons originating from the lateral hypothalamus activate a small population of GABAergic interneurons in the lateral habenula (LHb) via orexin receptor 2 (OxR2) to promote aggression and conditioned place preference (CPP) for aggression-paired contexts. Our study suggests that the orexin system is a potential target for the development of novel therapies aimed at reducing aggressive behaviors and provides the first functional evidence of a local inhibitory circuit within the LHb.

neuroscience↗

bioRxiv2019

Disruption of the CSF-1-CSF-1R axis alters cerebellar microglia and is associated with motor and social interaction defects

Microglia, the brain resident macrophages, critically shape forebrain neuronal circuits. However, their precise function in the cerebellum is unknown. Here we show that human and mouse cerebellar microglia express a unique molecular program distinct from forebrain microglia. Cerebellar microglial identity was driven by the CSF-1R ligand CSF-1, independently of the alternate CSF-1R ligand, IL-34. Accordingly, CSF-1 depletion from Nestin+ cells led to severe depletion and transcriptional alterations of cerebellar microglia, while microglia in the forebrain remained intact. Strikingly, CSF-1 deficiency and alteration of cerebellar microglia were associated with reduced Purkinje cells, altered neuronal function, and defects in motor learning and social novelty interactions. These findings reveal a novel CSF-1-CSF-1R signaling-mediated mechanism that contributes to motor function and social behavior.\n\nSummaryMicroglia are a heterogeneous population whose identity and function are dictated by signals from their microenvironment. Kana et al. show that CSF-1 signaling is critical for maintaining cerebellar microglial transcriptional identity and homeostasis, and that altering the CSF-1 - CSF-1R axis leads to motor and behavioral defects.

neuroscience↗

bioRxiv2017

The Spectral Features Of EEG Responses To Transcranial Magnetic Stimulation Of The Primary Motor Cortex Depend On The Amplitude Of The Motor Evoked Potentials

Transcranial magnetic stimulation (TMS) of the primary motor cortex (M1) can excite both cortico-cortical and cortico-spinal axons resulting in TMS-evoked potentials (TEPs) and motor-evoked potentials (MEPs), respectively. Despite this remarkable difference with other cortical areas, the influence of motor output and its amplitude on TEPs is largely unknown. Here we studied TEPs resulting from M1 stimulation and assessed whether their waveform and spectral features depend on the MEP amplitude. To this aim, we performed two separate experiments. In experiment 1, single-pulse TMS was applied at the same supra-threshold intensity on primary motor, prefrontal, premotor and parietal cortices and the corresponding TEPs were compared by means of local mean field power and time-frequency spectral analysis. In experiment 2 we stimulated M1 at resting motor threshold in order to elicit MEPs characterized by a wide range of amplitudes. TEPs computed from high-MEP and low-MEP trials were then compared using the same methods applied in experiment 1. In line with previous studies, TMS of M1 produced larger TEPs compared to other cortical stimulations. Notably, we found that only TEPs produced by M1 stimulation were accompanied by a late ([~]300 ms after TMS) event-related desynchronization (ERD), whose magnitude was strongly dependent on the amplitude of MEPs. Overall, these results suggest that M1 produces peculiar responses to TMS possibly reflecting specific anatomo-functional properties, such as the re-entry of proprioceptive feedback associated with target muscle activation.

neuroscience↗

bioRxiv2017

Experience-induced forgetting by WT1 enables learning of sequential tasks.

Under physiological conditions, strength and persistence of memory must be regulated in order to produce behavioral flexibility. In fact, impairments in memory flexibility are associated with pathologies such as post-traumatic stress disorder or autism; however the underlying mechanisms that enable memory flexibility are still poorly understood. Here we identified the transcriptional repressor Wilms Tumor 1 (WT1) as a critical synaptic plasticity regulator that decreases memory strength, promoting memory flexibility. WT1 was activated in the hippocampus following induction of long-term potentiation (LTP) or learning. WT1 knockdown enhanced CA1 neuronal excitability, LTP and long-term memory whereas its over-expression weakened memory retention. Moreover, forebrain WT1-deficient mice showed deficits in both reversal, sequential learning tasks and contextual fear extinction, exhibiting impaired memory flexibility. We conclude that WT1 limits memory strength or promotes memory weakening, thus enabling memory flexibility, a process that is critical for learning from new experience.

neuroscience↗