Biology subjects

Silva, A. P.

Publications and source records attributed to Silva, A. P..

5 recordsLinked to original sources

bioRxiv2024

Deciphering the impact of cancer cells secretome and its derived-peptide VGF on breast cancer brain metastasis

Brain metastases (BM) are one of the most serious clinical problems in breast cancer (BC) progression, associated with lower survival rates and a lack of effective therapies. Thus, to dissect the early stages of the brain metastatic process, we have searched for a brain-tropic metastatic signature on BC cells secretome, as a promising source for the discovery of new biomarkers involved in brain metastatic progression. Therefore, six specifically deregulated peptides were found to be enriched in the secretome of brain organotropic BC cells. Importantly, these secretomes caused significant blood-brain barrier (BBB) disruption, as well as microglial activation, in vitro and in vivo. We identified the VGF nerve growth factor inducible as a brain-specific peptide, promoting BBB dysfunction similar to the secretome of brain organotropic BC cells. Concerning microglial activation, a slight increase was also observed upon VGF treatment. In a series of human breast tumors, VGF was found to be expressed in both cancer cells and in the adjacent stroma. VGF-positive tumors showed a significant worse prognosis and were associated with HER2 overexpression and triple-negative molecular signatures. Finally, in a cohort including primary breast tumors and their corresponding metastatic locations to the lung, bone, and brain, we found that VGF significantly correlates with the brain metastatic site. In conclusion, we found a specific BC brain metastatic signature, where VGF was identified as a key mediator in this process. Importantly, its expression was associated with poor prognosis for BC patients, probably due to its associated increased risk of developing BM.

cancer biology↗

bioRxiv2023

Shifting KRAS hotspot mutations inhibition paradigm in colorectal cancer

KRAS hotspot mutations are difficult to target, highlighting the need of developing new specific target drugs for cancers driven by these mutations, like colorectal cancer (CRC). Here, we discover a new ruthenium compound, PMC79, that inhibits specifically mutated KRAS and the downstream signaling ERK and AKT proteins both "in vitro" and "in vivo". We demonstrated that PMC79 inhibits KRAS mutated kinase activity and is selective for KRAS mutations not affecting the KRAS wild-type protein. KRAS inhibition is not dependent on actin polymerization or on proteasome. Molecular docking analysis suggests that this effect might result from protein dynamics associated with the mutations. We demonstrated that low doses of PMC79 potentiate 5-fluorouracil anticancer effect. "In vivo" PMC79 "proof of concept" showed that it reduces tumor growth in the CAM-xenograft model and induces necrosis of the tumor in the xenograft mice model. PMC79 is a promising new "magic bullet" for CRCs harboring mutated KRAS.

pharmacology and toxicology↗

bioRxiv2023

Spiny but photogenic: amateur sightings complement herbarium specimens to reveal the bioregions of cacti

PremiseCacti are characteristic elements of the Neotropical flora and of major interest for biogeographic, evolutionary, and ecological studies. Here we test global biogeographic boundaries for Neotropical Cactaceae using specimen-based occurrences coupled with data from visual observations, including citizen science records, as a means to tackle the known collection biases in the family. MethodsSpecies richness and record density were assessed separately for preserved specimens and human observations and a bioregional scheme tailored to Cactaceae was produced using the interactive web application Infomap Bioregions based on data from 261,272 point records cleaned through automated and manual steps. Key ResultsWe find that areas in Mexico and southwestern USA, Eastern Brazil and along the Andean region have the greatest density of records and the highest species richness. Human observations complement information from preserved specimens substantially, especially along the Andes. We propose 24 cacti bioregions, among which the most species-rich are, in decreasing order: northern Mexico/southwestern USA, central Mexico, southern central Mexico, Central America, Mexican Pacific coast, central and southern Andes, northwestern Mexico/extreme southwestern USA, southwestern Bolivia, northeastern Brazil, Mexico/Baja California. ConclusionsThe bioregionalization proposed shows novel or modified biogeographical boundaries specific to cacti, and can thereby aid further evolutionary, biogeographic, and ecological studies by providing a validated framework for further analyses. This classification builds upon, and is distinctive from, other expert-derived regionalization schemes for other taxa. Our results showcase how observation data, including citizen-science records, can complement traditional specimen-based data for biogeographic research, particularly for taxa with specific specimen collection and preservation challenges and those that are threatened or internationally protected.

plant biology↗

bioRxiv2020

The Nucleosome Remodeling and Deacetylase complex has an asymmetric, dynamic, and modular architecture

The Nucleosome Remodeling and Deacetylase (NuRD) complex is essential for development in complex animals but has been refractory to biochemical analysis. We present the first integrated analysis of the architecture of the native mammalian NuRD complex, combining quantitative mass spectrometry, covalent cross-linking, protein biochemistry and electron microscopy. NuRD is built around a 2:2:4 pseudo-symmetric deacetylase module comprising MTA, HDAC and RBBP subunits. This module interacts asymmetrically with a remodeling module comprising one copy each of MBD, GATAD2 and CHD subunits. The previously enigmatic GATAD2 controls the asymmetry of the complex and directly recruits the ATP-dependent CHD remodeler. Unexpectedly, the MTA-MBD interaction acts as a point of functional switching. The transcriptional regulator PWWP2A modulates NuRD assembly by competing directly with MBD for binding to the MTA-HDAC-RBBP subcomplex, forming a moonlighting PWWP2A-MTA-HDAC-RBBP complex that likely directs deacetylase activity to PWWP2A target sites. Taken together, our data describe the overall architecture of the intact NuRD complex and reveal aspects of its structural dynamics and functional plasticity.

biochemistry↗

bioRxiv2017

Genetic ablation of RhoA in adult microglia causes synapse and neuronal loss

Nervous tissue homeostasis requires regulation of microglia activity. Using conditional gene targeting in mice, we demonstrate that genetic ablation of the small GTPase Rhoa in adult microglia is sufficient to trigger spontaneous microglia activation producing a neurological phenotype (including synapse and neuron loss, impairment of LTP, formation of {beta}-amyloid plaques and memory deficits). Mechanistically, loss of Rhoa in microglia triggers Src activation and Src-mediated Tnf production, leading to excitotoxic glutamate secretion. Inhibiting Src in microglia Rhoa-deficient mice attenuates microglia dysregulation and the ensuing neurological phenotype. We also found that the Rhoa/Src signaling pathway was disrupted in microglia of the APP/PS1 mouse model of Alzheimers disease and that low doses of A{beta} oligomers triggered microglia neurotoxic polarization through the disruption of Rhoa-to-Src signaling. Overall, our results indicate that disturbing RhoGTPase signaling in microglia can directly cause neurodegeneration.

neuroscience↗