Biology subjects

Suarez, R.

Publications and source records attributed to Suarez, R..

7 recordsLinked to original sources

bioRxiv2026

Medulloblastoma Forms Symbiotic Metabolic Partnerships with Macrophages to Establish Leptomeningeal Metastases

Leptomeningeal metastases are the primary source of morbidity and mortality for pediatric medulloblastoma patients. Due to limited surgical sampling of metastases in patients, little is understood of the mechanisms of metastasis. Here, we identify biologically distinct quiescent small metastases (designated as micrometastases) and mitotically active larger metastases (macrometastases). Macrometastases are more metabolically active than micrometastases and contain higher levels of lipids, particularly cholesterol. Macrometastases secrete CXCL12, which attracts lipid-laden macrophages into the tumor. Lipid-laden macrophages upregulate the cholesterol transporter ABCG1, promoting the efflux of free cholesterol, which is then taken up by tumor cells via the HDL receptor SCARB1. CXCL12-driven macrophage recruitment and exogenous cholesterol are sufficient and necessary to drive progression of medulloblastoma leptomeningeal metastases in vivo. High fat diets drive metastatic progression in vivo. Dietary or pharmacological interventions targeting the CXCL12-SCARB1-cholesterol axis represent therapeutic strategies to either prevent or treat medulloblastoma leptomeningeal metastases.

cancer biology↗

bioRxiv2025

Adaptive Evolution of Gene Regulatory Networks in Mammalian Neocortical Neurons

Mammals have evolved a plethora of adaptations that have enabled them to thrive in diverse environments. Among the most significant is the emergence of a more complex brain, exemplified by the dramatic transformation of the dorsal cortex from a single layer of excitatory projection neurons (ExNs) in ancestors to a multilayered cerebral neocortex enriched with diverse intratelencephalic (IT) and extratelencephalic (ET) ExN subtypes. These ExNs established specialized projection systems, such as the corticospinal tract and corpus callosum, enhancing brain connectivity and functionality. However, the evolutionary mechanisms underlying these mammalian-specific adaptations remain elusive. By comparing the landscape of gene expression and cis-regulatory elements (CREs) in mouse ExN subtypes and by cross-species examination of mammalian and non-mammalian CREs, we identified mammalian-specific CREs and expression patterns. The mammalian-specific CREs include a subset bound by ZBTB18 that are associated with genes defining IT and ET subtypes and connectivity. Both ZBTB18 and these target genes have previously been implicated in intellectual disability and autism. Deletion of Zbtb18 in mouse ExNs dysregulated target gene expression, reduced molecular diversity, diminished corticospinal and callosal projections, and increased intrahemispheric cortico-cortical association projections to the prefrontal cortex, resembling features of non-mammalian dorsal pallium. Interestingly, ZBTB18 binding motifs are highly enriched in callosally projecting IT-biased CREs, where they show higher conservation specifically in mammals. This study uncovers critical components and mammalian-specific evolutionary adaptations within a regulatory node essential for neocortical ExN identity and connectivity, with implications for neurodevelopmental and neuropsychiatric disorders.

neuroscience↗

bioRxiv2024

Lactate-carried Mitochondrial Energy Overflow

We addressed the question of mitochondrial lactate metabolism using genetically-encoded sensors. The organelle was found to contain a dynamic lactate pool that leads to dose- and time-dependent protein lactylation. In neurons, mitochondrial lactate reported blood lactate levels with high fidelity. The exchange of lactate across the inner mitochondrial membrane was found to be mediated by a high affinity H+-coupled transport system involving the mitochondrial pyruvate carrier MPC. Assessment of electron transport chain activity and determination of lactate flux showed that mitochondria are tonic lactate producers, a phenomenon driven by energization and stimulated by hypoxia. We conclude that an overflow mechanism caps the redox level of mitochondria, while saving energy in the form of lactate. One Sentence SummaryMitochondrial lactate production

biochemistry↗

bioRxiv2023

Cortical activity emerges in region-specific patterns during early brain development

The development of precise neural circuits in the brain requires spontaneous patterns of neural activity prior to functional maturation. In the rodent cerebral cortex patchwork and wave patterns of activity develop in somatosensory and visual regions, respectively, and are present at birth. However, whether such activity patterns occur in non-eutherian mammals, as well as when and how they arise during development remain open questions relevant to understand brain formation in health and disease. Since the onset of patterned cortical activity is challenging to study prenatally in eutherians, here we offer a new approach in a minimally invasive manner using marsupial dunnarts, whose cortex forms postnatally. We discovered similar patchwork and travelling waves in the dunnart somatosensory and visual cortices at stage 27 (equivalent to newborn mice), and examined progressively earlier stages of development to determine their onset and how they first emerge. We observed that these patterns of activity emerge in a region-specific and sequential manner, becoming evident as early as stage 24 in somatosensory and stage 25 in visual cortices (equivalent to embryonic day 16 and 17, respectively, in mice), as cortical layers establish and thalamic axons innervate the cortex. In addition to sculpting synaptic connections of existing circuits, evolutionarily conserved patterns of neural activity could therefore help regulate early events in cortical development. Significance StatementRegion-specific patterns of neural activity are present at birth in rodents and are thought to refine synaptic connections during critical periods of cerebral cortex development. Marsupials are born much more immature than rodents, allowing the investigation of how these patterns arise in vivo. We discovered that cortical activity patterns are remarkably similar in marsupial dunnarts and rodents, and that they emerge very early, before cortical neurogenesis is complete. Moreover, they arise from the outset in different patterns specific to somatosensory and visual areas (i.e., patchworks and waves) indicating they may also play evolutionarily conserved roles in cortical regionalization during development.

neuroscience↗

bioRxiv2020

The DCC receptor regulates astroglial development essential for telencephalic morphogenesis and corpus callosum formation

The forebrain hemispheres are predominantly separated during embryogenesis by the interhemispheric fissure (IHF). Radial astroglia remodel the IHF to form a continuous substrate between the hemispheres for midline crossing of the corpus callosum (CC) and hippocampal commissure (HC). DCC and NTN1 are molecules that have an evolutionarily conserved function in commissural axon guidance. The CC and HC are absent in Dcc and Ntn1 knockout mice, while other commissures are only partially affected, suggesting an additional aetiology in forebrain commissure formation. Here, we find that these molecules play a critical role in regulating astroglial development and IHF remodelling during CC and HC formation. Human subjects with DCC mutations display disrupted IHF remodelling associated with CC and HC malformations. Thus, axon guidance molecules such as DCC and NTN1 first regulate the formation of a midline substrate for dorsal commissures prior to their role in regulating axonal growth and guidance across it.

neuroscience↗

bioRxiv2020

DRAXIN regulates interhemispheric fissure remodelling to influence the extent of corpus callosum formation

Corpus callosum dysgenesis (CCD) is a congenital disorder that incorporates either partial or complete absence of the largest cerebral commissure. Remodelling of the interhemispheric fissure (IHF) provides a substrate for callosal axons to cross between hemispheres, and its failure is the main cause of complete CCD. However, it is unclear whether defects in this process could give rise to the heterogeneity of expressivity and phenotypes seen in human cases of CCD. We identify incomplete IHF remodelling as the key structural correlate for the range of callosal abnormalities in inbred and outcrossed BTBR mouse strains, as well as in humans with partial CCD. We identify an eight base pair deletion in Draxin and misregulated astroglial and leptomeningeal proliferation as genetic and cellular factors for variable IHF remodelling and CCD in BTBR acallosal strains. These findings support a model where genetic events determine corpus callosum structure by influencing leptomeningeal-astroglial interactions at the IHF.

neuroscience↗

bioRxiv2020

Optimized pseudotyping conditions for the SARS-COV2 Spike glycoprotein

The SARS-COV2 Spike glycoprotein is solely responsible for binding to the host cell receptor and facilitating fusion between the viral and host membranes. The ability to generate viral particles pseudotyped with SARS-COV2 Spike is useful for many types of studies, such as characterization of neutralizing antibodies or development of fusion-inhibiting small molecules. Here we characterized the use of a codon-optimized SARS-COV2 Spike glycoprotein for the generation of pseudotyped HIV-1, MLV, and VSV particles. The full-length Spike protein functioned inefficiently with all three systems but was enhanced over 10-fold by deleting the last 19 amino acids of the cytoplasmic tail of Spike. Infection of 293FT target cells was only possible if the cells were engineered to stably express the human ACE-2 receptor, but stably introducing an additional copy of this receptor did not further enhance susceptibility. Stable introduction of the Spike activating protease TMPRSS2 further enhanced susceptibility to infection by 5-10 fold. Substitution of the signal peptide of the Spike protein with an optimal signal peptide did not enhance or reduce infectious particle production. However, modification of a single amino acid in the furin cleavage site of Spike (R682Q) enhanced infectious particle production another 10-fold. With all enhancing elements combined, the titer of pseudotyped particles reached almost 106 infectious particles/ml. Finally, HIV-1 particles pseudotyped with SARS-COV2 Spike was successfully used to detect neutralizing antibodies in plasma from COVID-19 patients, but not plasma from uninfected individuals. ImportanceWhen working with pathogenic viruses, it is useful to have rapid quantitative tests for viral infectivity that can be performed without strict biocontainment restrictions. A common way of accomplishing this is to generate viral pseudoparticles that contain the surface glycoprotein from the pathogenic virus incorporated into a replication-defective viral particle that contains a sensitive reporter system. These pseudoparticles enter cells using the glycoprotein from the pathogenic virus leading to a readout for infection. Conditions that block entry of the pathogenic virus, such as neutralizing antibodies, will also block entry of the viral pseudoparticles. However, viral glycoproteins often are not readily suited for generating pseudoparticles. Here we describe a series of modifications that result in the production of relatively high titer SARS-COV2 pseudoparticles that are suitable for detection of neutralizing antibodies from COVID-19 patients.

microbiology↗