Biology subjects

Vazquez, A.

Publications and source records attributed to Vazquez, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Distinct population dimensions separate sensory adaptation and expectation-related signals in visual cortex

Mismatch negativity is conventionally quantified as a scalar response-amplitude difference between rare deviant and repeated standard stimuli, leaving its organization at the neuronal population level unresolved. We recorded population activity in mouse primary visual cortex (V1) during visual oddball and control paradigms while testing contributions from anterior cingulate cortex (ACC) input using optogenetic inhibition. Mismatch modulated firing rates bidirectionally and these changes largely canceled out on average, yet produced robustly separable population activity patterns. On the stimulus-encoding manifold, repeated standard exposure produced standard-specific response attenuation and a shared rotation of standard and deviant representations, revealing a component not isolated by conventional stimulus-specific adaptation and deviance-detection contrasts. Off the manifold, standards and deviants occupied opposing positions along an ACC-modulated axis consistent with expectation confirmation and violation. Thus, visual mismatch responses engage separable transformations of stimulus representations and expectation-related population activity, with ACC input selectively contributing to the latter while not significantly affecting stimulus encoding or on-manifold adaptation.

neuroscience↗

bioRxiv2026

Two-Dimensional Phase Separation of DNA Nanomotifs Anchored to Lipid Bilayers

Spatial organization and temporal regulation of membrane components are essential for achieving complex functions in artificial cells, such as cell division and signalling. DNA-based molecular tools provide a powerful means to control biomolecular interactions with high precision. Here, we investigate the phase behavior of cholesterol-modified, star-shaped DNA nanomotifs anchored to the lipid bilayers of giant unilamellar vesicles (GUVs), by using fluorescence confocal microscopy and cryo-electron microscopy. These motifs spontaneously anchor to the lipid bilayers via hydrophobic interactions and exhibit distinct spatial organization depending on their sticky end sequences. Motifs with complementary sticky end sequences interact and distribute uniformly, while orthogonal motifs with different sticky end sequences segregate into isolated gel-like domains with limited lateral mobility. Notably, the phase separation of motifs does not require lipid phase separation, indicating that DNA-driven organization can take place independently of lipid phase separation. The behavior of this system is governed by the interplay of three key parameters: (i) hydrophobic anchoring via cholesterol, (ii) electrostatic repulsion between negatively charged DNA nanomotifs, and (iii) sticky end interactions. The observed two-dimensional phase separation of orthogonal DNA nanomotifs at the GUV interface presents a novel strategy for controlling lateral membrane organization in GUV systems. This approach would offer flexibility in membrane composition and enables molecular positioning, thereby achieving a high degree of organization on the surface in artificial cell models.

biophysics↗

bioRxiv2026

Are mosquito species present in Spain competent for Oropouche virus?

Oropouche virus (OROV; Orthobunyavirus) is an emerging arbovirus endemic to South America and the Caribbean, with imported cases in European countries, including Spain. Although primarily transmitted by biting midges (Culicoides spp.), OROV has been detected in several mosquito species, raising concerns about potential establishment in non-endemic regions. European populations of Aedes albopictus, and Culex pipiens, as well as the invasive Aedes aegypti, represent relevant models for assessing vector competence. Here, we evaluated vector competence of Spanish Cx. pipiens biotype molestus, Spanish Ae. albopictus, and Ae. aegypti (Liverpool strain), for the 2024 OROV outbreak strain. Female mosquitoes were orally exposed to infectious blood meals and maintained under controlled insectary conditions. In addition, an additional group received a second non-infectious blood meal. The survival of the mosquitoes was monitored, and infection, dissemination, and transmission rates were assessed at 7-, 14-, and 21-days post-infection. Vertical transmission of the virus to the progenies was also analyzed. Overall, Ae. albopictus exhibited low infection rates, with occasional dissemination and transmission events. Aedes aegypti and Cx. pipiens showed infection and occasional dissemination, but no evidence of transmission. A second non-infectious blood meal did not significantly affect infection, dissemination, or transmission rates in any species. Viral loads in bodies and legs were low and did not differ significantly between species, time points, or feeding regimens. Survival was not affected by infection or blood-feeding regime. We did not find vertical transmission of OROV to the progenies. Regardless of virus dissemination in mosquitoes, our study indicates poor vector competence of Spanish Ae. albopictus and a lack of competence in Ae. aegypti and Cx. pipiens for the circulating OROV strain. These findings suggest a low risk for local OROV establishment in Spain, although continuous surveillance and research are warranted to monitor potential vector-virus adaptation.

microbiology↗

bioRxiv2026

Gain and loss of gut symbionts during stingless bee diversification is linked to host group size

Microbiomes typically vary between closely related host species, but how and why they diverge during host diversification remain poorly understood. Bees provide a well-established model for the role of sociality in microbiome evolution: solitary species have generalist gut bacterial symbionts, while eusocial honey bees and bumble bees have host-specific "core" gut bacterial symbionts. Curiously however, some species of stingless bees--the most diverse clade of eusocial bees--lack the core symbionts Snodgrassella and Gilliamella. Here, we tested whether group size, a fundamental trait of social organisms, explains symbiont gain and loss in stingless bees. Using specimens from a global collection, we performed 16S rRNA gene sequencing and qPCR on 187 adult workers representing 29 species and 18 genera. Maximum reported colony sizes for these species range from [~]100 to over [~]100,000 individuals. Our phylogenetic models indicate positive feedbacks between group size and the symbionts Snodgrassella and Gilliamella. We suggest that challenges faced by large groups (e.g., disease risk) may select for symbionts that supply needed functionality (e.g., pathogen protection). Our findings highlight group size as a potentially widespread driver of microbiome evolution in social hosts.

evolutionary biology↗

bioRxiv2024

Volumetric and Diffusion Tensor Imaging biomarkers indicating long lasting post-concussion abnormalities in a youth pig model of mild Traumatic Brain Injury

Mild Traumatic Brain Injury (mTBI) caused by sports-related incidents in children and youth can lead to prolonged cognitive impairments, underscoring the importance of improved diagnosis and comprehension of its enduring impacts on neuropathology. A pig model was chosen for its similarities to the human brain in terms of gyrencephalic structure, size, and regional proportions, and a closed-head mTBI was induced in adolescent pigs. In this study, 12 (n=4 male and n=8 female) 16-weeks old Yucatan pigs were tested; n=6 received mTBI and n=6 received a Sham procedure. This study utilized T1-weighted imaging to assess volumetric alterations in different regions of the brain and diffusion tensor imaging (DTI) to examine microstructural damage in white matter. The pigs were imaged at one and three months post-injury. Our volumetric analysis of key white and gray matter regions showed significant longitudinal changes in pigs with mTBI compared to sham controls. The observed volume increases may be attributed to swelling, neuroinflammation, or hyperactivity. Fractional anisotropy (FA) values derived from DTI images demonstrated an increase in corpus callosum from 1 month to 3 months only in mTBI pigs. Additionally, comparisons of the left and right internal capsules revealed a decrease in FA in the right internal capsule for mTBI pigs, likely due to the impact being slightly localized to the right side of the brain, which may indicate demyelination. Thus, the injury has disrupted the maturation of white and gray matter of the developing brain. This signifies the need for longitudinal investigations after mTBI to comprehensively assess its long-term effects and contribute to the clinical management of concussion in youth.

bioengineering↗

bioRxiv2024

Geometrically balanced model of cell growth

The proteome balance constraint in metabolic flux balance analysis asserts that the proteome is constructed by ribosomes, which themselves contain many proteins. This leads to a fundamental question of optimal allocation of limited proteome among different pools of enzymes, which include ribosomes themselves. However, recent work points to additional constraints imposed by the cell geometry. In this paper we deduce the proteogeometric constraint [Formula], where{pi} A,{pi} P and{pi} L are the proteomic fractions allocated to the cell surface area, protein synthesis and cell membrane phospholipids synthesis and [Formula] and{theta} are constants imposed by geometry of the cell. We illustrate the relevance of this constraint using a reduced model of cell metabolism, illuminating the interplay between cell metabolism and cell geometry.

systems biology↗

bioRxiv2024

Antigen-Specific T Cell Receptor Discovery for Treating Progressive Multifocal Leukoencephalopathy

BackgroundProgressive multifocal leukoencephalopathy (PML) is a frequently fatal disease of the central nervous system caused by JC virus (JCV). Survival is dependent on early diagnosis and ability to re-establish anti-viral T cell immunity. Adoptive transfer of polyomavirus-specific T cells has shown promise; however, there are no readily available HLA-matched anti-viral T cells to facilitate rapid treatment. ObjectiveIdentify epitopes of the JCV major capsid protein VP1 that elicit an immune response in the context of human leukocyte antigen allele A*02:01 (HLA-A2) and isolate cognate T cell receptors (TCRs) from healthy donors. Evaluate individual VP1-specific TCRs for their capacity to be expressed in T cells and clear JCV in vitro. MethodsPBMCs from HLA-A2+ healthy donors were stimulated with peptide libraries tiled across the JCV VP1 protein. Multiple rounds of stimulation were performed to identify the antigens that induced the largest expansion and CD8+ T cell response (measured as INF{gamma}, TNF, CD137, and CD69 expression). High-affinity, antigen-specific CD8+ T cells were isolated based on intensity of tetramer binding for downstream single-cell TCR sequencing. Candidate TCRs were selected based on tetramer binding affinity and activation assays. Promising TCRs were introduced into the T cell genome via viral transduction for in vitro validation including peptide-pulsed K562 cells and astrocyte cells, and JCV-infected astrocytes. ResultsFour conserved JCV VP1 epitopes (amino acids 100-108, 251-259, 253-262, and 274-283) presented by HLA-A2 were identified. VP1(100-108) consistently elicited the highest level of IFN-{gamma} production from multiple donors and this peptide is in a highly conserved region of VP1. We next identified fourteen high avidity TCRs specific for VP1(100-108). When virally transduced into primary human T cells, seven of these TCRs demonstrated specific binding to VP1(100-108):HLA-A2 tetramers, and four showed increased IFN-{gamma} response when incubated with peptide. Primary CD8+ T cells expressing two of these TCRs cleared both HLA-A2 positive K562 cells and HLA-A2 positive SVG astrocyte cell line presenting exogenously added VP1 peptide at a range of E:T ratios. In addition, both TCR-transduced T cell populations effectively lysed JCV-infected astrocytes. ConclusionsWe identified JCV VP1 epitopes that are immunogenic in the context of HLA-A2 MHC-I, including epitopes that have not been previously described. The VP1(100-108) epitope was used to isolate HLA-A2-restricted TCRs. When cloned into primary human CD8+ T cells, these TCRs recognized VP1 (100-108)-presenting targets, and the transduced T cells conferred cytotoxic activity and eliminated K562 and astrocyte cells displaying the VP1(100-108) peptide and not sham peptide, as well as JCV-infected astrocytes. Taken together, these data suggest that JCV VP1-specific TCRs could be appealing therapeutics for HLA-A2+ individuals with PML in whom intrinsic T cell immunity cannot be rescued.

neuroscience↗

bioRxiv2024

Impact of life origins on metabolism

Living organisms are defined by self-replication and self-confinement. We expect these two properties to shape the metabolic capabilities of cells. Here I demonstrate that the maximum growth rate of cells is, in a first approximation, the geometric mean between the maximum rate of ribosome self-replication and the maximum rate of macromolecular synthesis allowed by the interior volume defined by the cell membrane. I also show how these constraints are buried into the biomass compositions of flux balance models.

biophysics↗

bioRxiv2024

Differential roles of putative arginine fingers of AAA+ ATPases Rvb1 and Rvb2

The evolutionarily conserved AAA+ ATPases Rvb1 and Rvb2 proteins form a heteromeric complex (Rvb1/2) required for assembly or remodeling of macromolecular complexes in essential cellular processes ranging from chromatin remodeling to ribosome biogenesis. Rvb1 and Rvb2 have a high degree of sequence and structural similarity, and both contain the classical features of ATPases of their clade, including an N-terminal AAA+ subdomain with the Walker A motif, an insertion domain that typically interacts with various binding partners, and a C-terminal AAA+ subdomain containing a Walker B motif, the Sensor I and II motifs, and an arginine finger. In this study, we find that despite the high degree of structural similarity, Rvb1 and Rvb2 have distinct active sites that impact their activities and regulation within the Rvb1/2 complex. Using a combination of biochemical and genetic approaches, we show that replacing the homologous arginine fingers of Rvb1 and Rvb2 with different amino acids not only has distinct effects on the catalytic activity of the complex, but also impacts cell growth, and the Rvb1/2 interactions with binding partners. Using molecular dynamics simulations, we find that changes near the active site of Rvb1 and Rvb2 cause long-range effects on the protein dynamics in the insertion domain, suggesting a molecular basis for how enzymatic activity within the catalytic site of ATP hydrolysis can be relayed to other domains of the Rvb1/2 complex to modulate its function. Further, we show the impact that the arginine finger variants have on snoRNP biogenesis and validate the findings from molecular dynamics simulations using a targeted genetic screen. Together, our results reveal new aspects of the regulation of the Rvb1/2 complex by identifying a relay of long-range molecular communication from the ATPase active site of the complex to the binding site of cofactors. Most importantly, our findings suggest that despite high similarity and cooperation within the same protein complex, the two proteins have evolved with unique properties critical for the regulation and function of the Rvb1/2 complex. SignificanceAAA ATPases constitute a large family of proteins involved in various essential cellular functions in living organisms in all kingdoms of life. Members of this family typically form homo or hetero multimers that convert the energy from ATP hydrolysis to mechanical work. How the conserved features of AAA ATPases relay the energy from ATP hydrolysis to other functional domains of the complex remains largely unknown. Here, using arginine finger variants of Rvb1 and Rvb2, two evolutionarily conserved closely related AAA+ ATPases that form a heterohexameric complex, we reveal how individual protomers in a heteromeric complex can uniquely contribute to the overall function of the complex and how changes in the ATP binding site can be relayed to distal functional domains.

biochemistry↗

bioRxiv2024

Developmental disruption of Mef2c in Medial Ganglionic Eminence-derived cortical inhibitory interneurons impairs cellular and circuit function

MEF2C is strongly linked to various neurodevelopmental disorders (NDDs) including autism, intellectual disability, schizophrenia, and attention-deficit/hyperactivity. Mice constitutively lacking one copy of Mef2c, or selectively lacking both copies of Mef2c in cortical excitatory neurons, display a variety of behavioral phenotypes associated with NDDs. The MEF2C protein is a transcription factor necessary for cellular development and synaptic modulation of excitatory neurons. MEF2C is also expressed in a subset of cortical GABAergic inhibitory neurons, but its function in those cell types remains largely unknown. Using conditional deletions of the Mef2c gene in mice, we investigated the role of MEF2C in Parvalbumin-expressing Interneurons (PV-INs), the largest subpopulation of cortical GABAergic cells, at two developmental timepoints. We performed slice electrophysiology, in vivo recordings, and behavior assays to test how embryonic and late postnatal loss of MEF2C from GABAergic interneurons impacts their survival and maturation, and alters brain function and behavior. We found that loss of MEF2C from PV-INs during embryonic, but not late postnatal, development resulted in reduced PV-IN number and failure of PV-INs to molecularly and synaptically mature. In association with these deficits, early loss of MEF2C in GABAergic interneurons lead to abnormal cortical network activity, hyperactive and stereotypic behavior, and impaired cognitive and social behavior. Our findings indicate that MEF2C expression is critical for the development of cortical GABAergic interneurons, particularly PV-INs. Embryonic loss of function of MEF2C mediates dysfunction of GABAergic interneurons, leading to altered in vivo patterns of cortical activity and behavioral phenotypes associated with neurodevelopmental disorders.

neuroscience↗

bioRxiv2024

Requirements for efficient endosomal escape by designed mini-proteins

ZF5.3 is a compact, rationally designed mini-protein that escapes efficiently from the endosomes of multiple cell types. Despite its small size (27 amino acids), ZF5.3 can be isolated intact from the cytosol of treated cells and guides multiple classes of proteins into the cytosol and/or nucleus. In the best cases, delivery efficiencies reach or exceed 50% to establish nuclear or cytosolic concentrations of 500 nM or higher. But other than the requirement for unfoldable cargo and an intact HOPS complex, there is little known about how ZF5.3 traverses the limiting endocytic membrane. Here we delineate the attributes of ZF5.3 that enable efficient endosomal escape. We confirm that ZF5.3 is stable at pH values between 5.5 and 7.5, with no evidence of unfolding even at temperatures as high as 95 {degrees}C. The high-resolution NMR structure of ZF5.3 at pH 5.5, also reported here, shows a canonical p zinc-finger fold with the penta-arg motif integrated seamlessly into the C-terminal -helix. At lower pH, ZF5.3 unfolds cooperatively as judged by both circular dichroism and high-resolution NMR. Unfolding occurs upon protonation of a single Zn(II)-binding His side chain whose pKa corresponds almost exactly to that of the late endosomal lumen. pH-induced unfolding is essential for endosomal escape, as a ZF5.3 analog that remains folded at pH 4.5 fails to efficiently reach the cytosol, despite high overall uptake. Finally, using reconstituted liposomes, we identify a high-affinity interaction of ZF5.3 with a specific lipid-BMP-that is selectively enriched in the inner leaflet of late endosomal membranes. This interaction is 10-fold stronger at low pH than neutral pH, providing a molecular picture for why escape occurs preferentially and in a HOPS-dependent manner from late endosomal compartments. The requirements for programmed endosomal escape identified here should aid and inform the design of proteins, peptidomimetics, and other macromolecules that reach cytosolic or nuclear targets intact and at therapeutically relevant concentrations.

biochemistry↗

bioRxiv2023

Neuromelanin accumulation drives endogenous synucleinopathy in non-human primates

Although neuromelanin (NMel) is a dark pigment characteristic of dopaminergic neurons in the human substantia nigra pars compacta (SNpc), its potential role in the pathogenesis of Parkinsons disease (PD) has often been neglected since most commonly used laboratory animals lack NMel. Here we took advantage of adeno-associated viral vectors encoding the human tyrosinase gene for triggering a time-dependent NMel accumulation within SNpc dopaminergic neurons in macaques up to similar levels of pigmentation as observed in elderly humans. Furthermore, NMel accumulation induced an endogenous synucleinopathy mimicking intracellular inclusions typically observed in PD together with a progressive degeneration of NMel-expressing dopaminergic neurons. Moreover, Lewy body-like intracellular inclusions were observed in cortical areas of the frontal lobe receiving dopaminergic innervation, supporting a circuit-specific anterograde spread of endogenous synucleinopathy by permissive trans-synaptic templating. In summary, the conducted strategy resulted in the development and characterization of a new macaque model of PD matching the known neuropathology of this disorder with unprecedented accuracy. Most importantly, evidence is provided showing that intracellular aggregation of endogenous alpha-synuclein is triggered by NMel accumulation, therefore any therapeutic approach intended to decrease NMel levels may provide appealing choices for the successful implementation of novel PD therapeutics.

neuroscience↗

bioRxiv2023

Rewiring of the host cell metabolome and lipidome during lytic gammaherpesvirus infection is essential for infectious virus production

Oncogenic virus infections are estimated to cause [~]15% of all cancers. Two prevalent human oncogenic viruses are members of the gammaherpesvirus family: Epstein Barr Virus (EBV) and Kaposis Sarcoma Herpesvirus (KSHV). We use murine herpesvirus 68 (MHV-68), which shares significant homology with KSHV and EBV, as a model system to study gammaherpesvirus lytic replication. Viruses implement distinct metabolic programs to support their life cycle, such as increasing the supply of lipids, amino acids, and nucleotide materials necessary to replicate. Our data define the global changes in the host cell metabolome and lipidome during gammaherpesvirus lytic replication. Our metabolomics analysis found that MHV-68 lytic infection induces glycolysis, glutaminolysis, lipid metabolism, and nucleotide metabolism. We additionally observed an increase in glutamine consumption and glutamine dehydrogenase protein expression. While both glucose and glutamine starvation of host cells decreased viral titers, glutamine starvation led to a greater loss in virion production. Our lipidomics analysis revealed a peak in triacylglycerides early during infection and an increase in free fatty acids and diacylglyceride later in the viral life cycle. Furthermore, we observed an increase in the protein expression of multiple lipogenic enzymes during infection. Interestingly, pharmacological inhibitors of glycolysis or lipogenesis resulted in decreased infectious virus production. Taken together, these results illustrate the global alterations in host cell metabolism during lytic gammaherpesvirus infection, establish essential pathways for viral production, and recommend targeted mechanisms to block viral spread and treat viral induced tumors. IMPORTANCEViruses are intracellular parasites which lack their own metabolism, so they must hijack host cell metabolic machinery in order to increase the production of energy, proteins, fats, and genetic material necessary to replicate. Using murine herpesvirus 68 (MHV-68) as a model system to understand how similar human gammaherpesviruses cause cancer, we profiled the metabolic changes that occur during lytic MHV-68 infection and replication. We found MHV-68 infection of host cells increases glucose, glutamine, lipid, and nucleotide metabolic pathways. We also showed inhibition or starvation of glucose, glutamine or lipid metabolic pathways results in an inhibition of virus production. Ultimately, targeting changes in host cell metabolism due to viral infection can be used to treat gammaherpesvirus induced cancers and infections in humans.

microbiology↗

bioRxiv2022

Mitochondrial folate metabolism inhibition drives differentiation through mTORC1 mediated purine sensing

Supporting cell proliferation through nucleotide biosynthesis is an essential requirement for cancer cells. Hence, inhibition of folate-mediated one carbon (1C) metabolism, which is required for nucleotide synthesis, has been successfully exploited in anti-cancer therapy. Here, we reveal that mitochondrial folate metabolism is upregulated in patient-derived leukaemic stem cells (LSCs). We demonstrate that inhibition of mitochondrial 1C metabolism through impairment of de novo purine synthesis has a cytostatic effect on chronic myeloid leukaemia (CML) cells. Consequently, changes in purine nucleotide levels lead to activation of AMPK signalling and suppression of mTORC1 activity. Notably, suppression of mitochondrial 1C metabolism increases expression of erythroid differentiation markers. Moreover, we find that increased differentiation occurs independently of AMPK signalling and can be reversed through reconstitution of purine levels and reactivation of mTORC1. Of clinical relevance, we identify that combination of 1C metabolism inhibition with imatinib, a frontline treatment for CML patients, decreases the number of therapy-resistant CML LSCs in a patient-derived xenograft model. Our results highlight a novel role for folate metabolism and purine sensing in stem cell fate decisions and leukaemogenesis.

cancer biology↗

bioRxiv2022

Genomic accordions may hold the key to Monkeypox Clade IIb's increased transmissibility

The currently expanding monkeypox epidemic is caused by a subclade IIb descendant of a monkeypox virus (MPXV) lineage traced back to Nigeria in 1971. In contrast to monkeypox cases caused by clade I and subclade IIa MPXV, the prognosis of current cases is generally favorable, but person-to-person transmission is much more efficient. MPXV evolution is driven by selective pressure from hosts and loss of virus-host interacting genes. However, there is no satisfactory genetic explanation using single-nucleotide polymorphisms (SNPs) for the observed increased MPXV transmissibility. We hypothesized that key genomic changes may occur in the genomes low-complexity regions (LCRs), which are highly challenging to sequence and have been dismissed as uninformative. Using a combination of highly sensitive techniques, we determined a first high-quality MPXV genome sequence of a representative of the current epidemic with LCRs resolved at unprecedented accuracy. This effort revealed significant variation in short-tandem repeats within LCRs. We demonstrate that LCR entropy in the MPXV genome is significantly higher than that of SNPs and that LCRs are not randomly distributed. In silico analyses indicate that expression, translation, stability, or function of MPXV orthologous poxvirus genes (OPGs) 153, 204, and 208 could be affected in a manner consistent with the established "genomic accordion" evolutionary strategies of orthopoxviruses. Consequently, we posit that genomic studies focusing on phenotypic MPXV clade-/subclade-/lineage-/strain differences should change their focus to the study of LCR variability instead of SNP variability.

genomics↗

bioRxiv2021

Mitochondrial One-Carbon Flux has a Growth-Independent Role in Promoting Breast Cancer Metastasis

Progression of primary cancer to metastatic disease is the most common cause of death in cancer patients with minimal treatment options available. Canonical drugs target mainly the proliferative capacity of cancer cells, which often leaves slow-proliferating, persistent cancer cells unaffected. Metabolic determinants that contribute to growth-independent functions supporting resistance and metastatic dissemination are still poorly understood. In the present study, we revealed that antifolate treatment results in an uncoupled and autarkic mitochondrial one-carbon (1C) metabolism allowing sustained serine catabolism and formate overflow when cytosolic 1C metabolism is impaired. Interestingly, antifolate dependent growth-arrest did not correlate with decreased migration capacity. Therefore, using the antifolate Methotrexate as a tool compound allowed us to disentangle proliferation and migration to profile the metabolic phenotype of migrating (growth-arrested) cells. Supported by an increased NAD/NADH ratio, we observed increased serine de novo synthesis and increased serine catabolism to formate. Consequently, inhibition of serine de novo synthesis using the competitive PHGDH-inhibitor BI-4916 or direct inhibition of mitochondrial 1C metabolism reduced cancer cell migration. Using an orthotopic breast cancer model, we show that sole inhibition of mitochondrial serine catabolism does not affect primary tumor growth but strongly inhibits pulmonary metastasis. We conclude that mitochondrial 1C metabolism, despite being dispensable for proliferative capacities, confers an advantage to cancer cells by supporting their motility potential. Our results improve our understanding of 1C metabolism and of metabolic determinants that support the process of cancer cell migration and metastasis.

cancer biology↗

bioRxiv2020

Dietary and pharmacological induction of serine synthesis genes

There is an increasing interest in the pathway of L-serine synthesis and its. Although L-serine and downstream products can be obtained from the diet, serine deficiency has been documented in neurological disorders, macular degeneration and aging. This evidence calls for strategies to induce serine synthesis. Here I address this problem taking advantage of the wealth of data deposited in the gene expression omnibus database. I uncover that low protein and ketogenic diets increase the expression of serine synthesis genes in the liver and the brain relative to control diets. I discover oestrogen medications, the antifolate methotrexate and serine synthesis inhibitors as classes of compounds inducing the expression of serine synthesis genes in the liver. Future work is required to investigate the use of these interventions for the management of serine deficiency disorders.Competing Interest StatementThe authors have declared no competing interest.View Full Text

systems biology↗

bioRxiv2020

Discovering compounds mimicking calorie restriction using mammalian gene expression profiles

Obesity is a risk factor for cardiovascular diseases, diabetes and cancer. In theory the obesity problem could be solve by the adherence to a calorie restricted diet, but that is not generally achieved in practice. An alternative is a pharmacological approach, using compounds that trigger the same metabolic changes associated with calorie restriction. Here I expand in the pharmacological direction by identifying compounds that induce liver gene signature profiles that mimic those induced by calorie restriction. Using gene expression profiles from mice and rat I identify corticosteroids, PPAR agonists and some antibacterial/antifungal as candidate compounds mimicking the response to calorie restriction in the liver gene signatures. Liver gene signature analysis can be used to identify compounds that mimic calorie restriction.

systems biology↗