Biology subjects

Vasquez, M.

Publications and source records attributed to Vasquez, M..

9 recordsLinked to original sources

bioRxiv2025

Site-Specific Immune and Stromal Architecture Drive Resistance to Trastuzumab Deruxtecan in HER2+ Metastatic Breast Cancer

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) that has demonstrated remarkable efficacy in HER2+ and HER2-low metastatic breast cancer (mBC). Yet, 40-50% of patients fail to respond, and mechanisms underlying resistance, particularly those involving the immune microenvironment, remain poorly understood. To address this gap, we conducted spatial proteomic profiling of metastatic lesions from 25 HER2+ mBC patients treated with T-DXd, using the Bruker GeoMX Digital Spatial Profiler (DSP) platform. Regions of interest (ROIs) were segmented by CD45 expression to distinguish immune-rich versus immune-poor compartments, and spatial marker expression was compared between responders (R) and non-responders (NR). Spearman correlation analysis was used to assess spatial coordination among HER2, fibronectin, and immune markers. Non-responders exhibited greater HER2 heterogeneity, lower CD45+ immune infiltration, and consistent upregulation of fibronectin and granzyme B. In both bone and brain metastases, NR tissues showed strong correlations between fibronectin and T cell markers, indicating spatial immune exclusion. In contrast, NR lymph node metastases displayed negative correlations between fibronectin and immune markers and uncoordinated B-T cell clustering, suggesting an alternative resistance mechanism rooted in immune disorganization rather than exclusion. Collectively, these results implicate HER2 heterogeneity, fibrotic immune exclusion, and immune suppression as key drivers of T-DXd resistance across metastatic sites. By integrating spatial proteomics with clinical outcomes, this study provides novel insights into the spatial immune landscape of ADC resistance and identifies actionable biomarkers for patient stratification and combination therapy design, laying a critical foundation for developing biomarker-guided therapies and personalized treatment strategies to overcome ADC resistance in metastatic breast cancer. Translational SignificanceT-DXd represents a major advance in antibody-drug conjugate (ADC) therapies to address HER2 heterogeneity in tumors through bystander killing. However, treatment options following resistance to T-DXd remain limited, leaving a critical unmet need. As new ADCs continue to emerge, resistance will likely remain a persistent challenge across tumor types. This work extends beyond T-DXd resistance--it provides a framework to address resistance mechanisms common to other ADCs. By investigating immune-mediated mechanisms of ADC resistance, this research identifies therapeutic targets that can be leveraged to develop new treatment strategies. By integrating spatial biology with clinical data, this study offers unprecedented insights into immune-tumor interactions within the resistant tumor microenvironment. This approach deepens mechanistic understanding and enables personalized treatment strategies guided by spatially resolved biomarkers. This novel combination of spatial mechanistic research with clinical data represents advancement toward overcoming ADC resistance and improving outcomes for patients with few therapeutic options.

cancer biology↗

bioRxiv2025

Development and evaluation of screwworm, Cochliomyia hominivorax, transgenic sexing strains with embryonic gene promoters for a genetic control program

The New World screwworm, Cochliomyia hominivorax, was eradicated from North and Central America through the first application of the sterile insect technique. The sterile screwworm adult fly releases were mixed sex, but experience with other flies suggests that releasing only males could be up to five times more effective. Here we describe screwworm transgenic sexing strains (TSSs) with expected embryo lethality developed using the Tetracycline-off (Tet-off) system with the Lucilia cuprina nullo (DR6) or C. macellaria CG14427 (DR7) gene promoters and a tTA activated effector to promote female lethality. The TSSs expressed tTA highest in 2-3 h embryos and low in larvae and adults. However, most strains showed high expression in pupae. Evaluation on two doxycycline (Dox) regimens found that inclusion of Dox in the last larval feeding rescued females of the subsequent generation, likely by maternal Dox transfer to embryos. All TSSs produced only males on a reduced Dox feeding regimen but the female lethal period for the DR6 TSS was too late in development to save diet costs. Production parameters were met by all strains in colony, but strains had lower male fly survival than current production strains after removing Dox. In non-competitive mating success trials DR6 strains performed poorly, but DR7 performed equally to production strain males. However, males from all TSSs faired poorly in mating competition tests against production males. Our study highlights the importance of tightly-regulated gene promoters and suitable antibotics feeding schemes for the development and evaluation of TSSs based on Tet-off system.

biochemistry↗

bioRxiv2024

Estimating Propulsion Kinetics in Absence of a Direct Measurement of the Anterior Component of Ground Reaction Force

Anterior ground reaction force (AGRF) is a common measurement of walking function in post-stroke individuals. It is typically measured using multi-axis force-plates which are not always found in robotic research labs. Here we present a comparison of models using kinematic and kinetic metrics of propulsion to estimate AGRF. Nine models using measurements of maximum vertical ground reaction force (maxVGRF), vertical ground reaction force at peak AGRF (aVGRF), maximum trailing limb angle (maxTLA), trailing limb angle at peak AGRF (aTLA) and stride length (SL) were used to predict different metrics of propulsion kinetics, including maximum AGRF (maxAGRF), propulsive impulse (PI), maximum AGRF normalized by body-weight (maxAGRFnorm), and normalized PI (PInorm) from participants at speeds [0.6 1.4] m/s. R2 and AICc scores were recorded for each model, and the individual participant R2 values for the best single and two-factor models for each outcome were examined. Of the single-factor models, kinematic measurements were the best predictors of the outcome measurements. More specifically, maxAGRF/norm were best predicted by SL (R2 = 0.91, 0.82, respectively), and PI/norm were best predicted by maxTLA (R2 = 0.84, 0.43, respectively). For the two-factor models, maxAGRFnorm and PInorm were both best predicted by SL and aVGRFnorm, and maxVGRF yeilded the best predictions for maxAGRF and PI. Models predicting maxAGRF/norm better fit individual participants than those predicting PI/norm. These results indicate that maxAGRF can be estimated with reasonable accuracy (R2 = 0.92, RMSE of residuals: 1.5% bodyweight, equivalent to a 0.09 m/s increase in velocity) in the absence of a direct measurement of AGRF using both kinematic and kinetic measurements of propulsion.

bioengineering↗

bioRxiv2023

KRAS inhibition activates an actionable CD24 do-not-eat-me signal in pancreas cancer

KRASG12C inhibitors (G12Ci) have produced encouraging, albeit modest and transient, clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment is therefore crucial. To better understand the function of KRASG12C and possible G12Ci bypass mechanisms, we developed an autochthonous KRASG12C- driven PDAC model. Compared to the classical KRASG12D PDAC model, the G12C model exhibits slower tumor growth, yet similar histopathological and molecular features. Aligned with clinical experience, G12Ci treatment of KRASG12C tumors produced modest impact despite stimulating a hot tumor immune microenvironment. Immunoprofiling revealed that CD24, a dont eat me signal, is significantly upregulated on cancer cells upon G12Ci treatment. Blocking CD24 enhanced macrophage phagocytosis of cancer cells and significantly sensitized tumors to G12Ci treatment. Similar findings were observed in KRASG12D-driven PDAC. Together, this study reveals common and distinct oncogenic KRAS allele-specific biology and identifies a clinically actionable adaptive mechanism that may improve the efficacy of oncogenic KRAS inhibitor therapy in PDAC. SignificanceGeneration of an autochthonous KRASG12C-driven pancreatic cancer model enabled elucidation of specific effects of KRASG12C during tumor development, revealing CD24 as an actionable adaptive mechanism in cancer cells induced upon KRASG12C inhibition.

cancer biology↗

bioRxiv2021

Integration of GWAS and TWAS to elucidate the genetic architecture of natural variation for leaf cuticular conductance in maize

The cuticle, a hydrophobic layer of cutin and waxes synthesized by plant epidermal cells, is the major barrier to water loss when stomata are closed. Dissecting the genetic architecture of natural variation for maize leaf cuticular conductance (gc) is important for identifying genes relevant to improving crop productivity in drought-prone environments. To this end, we performed an integrated genome- and transcriptome-wide association study (GWAS/TWAS) to identify candidate genes putatively regulating variation in leaf gc. Of the 22 plausible candidate genes identified, five were predicted to be involved in cuticle precursor biosynthesis and export, two in cell wall modification, nine in intracellular membrane trafficking, and seven in the regulation of cuticle development. A gene encoding an INCREASED SALT TOLERANCE1-LIKE1 (ISTL1) protein putatively involved in intracellular protein and membrane trafficking was identified in GWAS and TWAS as the strongest candidate causal gene. A set of maize nested near-isogenic lines that harbor the ISTL1 genomic region from eight donor parents were evaluated for gc, confirming the association between gc and ISTL1 in a haplotype-based association analysis. The findings of this study provide novel insights into the role of regulatory variants in the development of the maize leaf cuticle, and will ultimately assist breeders to develop drought-tolerant maize for target environments. Sentence summaryWe performed an integrated GWAS/TWAS and identified 22 candidate genes putatively regulating variation in maize leaf gc. The association between gc and the strongest candidate causal gene, ISTL1, was validated with maize nested near-isogenic lines.

genetics↗

bioRxiv2020

The mitochondrial genomes of 11 aquatic macroinvertebrate species from Cyprus

Aquatic macroinvertebrates are often identified based on morphology, but molecular approaches like DNA barcoding, metabarcoding and metagenomics are increasingly used for species identification. These approaches require the availability of DNA references deposited in public databases. Here we report the mitochondrial genomes of 11 aquatic macroinvertebrates species from Cyprus, a European Union island country in the Mediterranean. Only three of the molecularly identified species could be assigned to a species name, highlighting the need for taxonomic work that leads to the formal description and naming of species, and the need for further genetic work to fill the current gaps in reference databases containing aquatic macroinvertebrates.Competing Interest StatementThe authors have declared no competing interest.View Full Text

molecular biology↗

bioRxiv2019

Genome-wide association study for maize leaf cuticular conductance identifies candidate genes involved in the regulation of cuticle development

The cuticle, a hydrophobic layer of cutin and waxes synthesized by plant epidermal cells, is the major barrier to water loss when stomata are closed at night and under water-limited conditions. Elucidating the genetic architecture of natural variation for leaf cuticular conductance (gc) is important for identifying genes relevant to improving crop productivity in drought-prone environments. To this end, we conducted a genome-wide association study of gc of adult leaves in a maize inbred association panel that was evaluated in four environments (Maricopa, AZ, and San Diego, CA in 2016 and 2017). Five genomic regions significantly associated with gc were resolved to seven plausible candidate genes (ISTL1, two SEC14 homologs, cyclase-associated protein, a CER7 homolog, GDSL lipase, and {beta}-D-XYLOSIDASE 4). These candidates are potentially involved in cuticle biosynthesis, trafficking and deposition of cuticle lipids, cutin polymerization, and cell wall modification. Laser microdissection RNA sequencing revealed that all these candidate genes, with the exception of the CER7 homolog, were expressed in the zone of the expanding adult maize leaf where cuticle maturation occurs. With direct application to genetic improvement, moderately high average predictive abilities were observed for whole-genome prediction of gc in locations (0.46 and 0.45) and across all environments (0.52). The findings of this study provide novel insights into the genetic control of gc and have the potential to help breeders more effectively develop drought-tolerant maize for target environments.\n\nArticle summaryThe cuticle serves as the major barrier to water loss when stomata are closed at night and under water-limited conditions and potentially relevant to drought tolerance in crops. We performed a genome-wide association study to elucidate the genetic architecture of natural variation for maize leaf cuticular conductance. We identified epidermally expressed candidate genes that are potentially involved in cuticle biosynthesis, trafficking and deposition, cutin polymerization, and cell wall modification. Finally, we observed moderately high predictive abilities for whole-genome prediction of leaf cuticular conductance. Collectively, these findings may help breeders more effectively develop drought-tolerant maize.

genetics↗

bioRxiv2019

Systems-wide analysis unravels the new roles of CCM signal complex (CSC)

Cerebral cavernous malformations (CCMs) are characterized by abnormally dilated intracranial capillaries that result in increased susceptibility to stroke. Three genes have been identified as causes of CCMs; KRIT1 (CCM1), MGC4607 (CCM2) and PDCD10 (CCM3); one of them is disrupted in most CCM cases. It was demonstrated that both CCM1 and CCM3 bind to CCM2 to form a CCM signaling complex (CSC) to modulate angiogenesis. In this report, we deployed both RNA-seq and proteomic analysis of perturbed CSC after depletion of one of three CCM genes to generate interactomes for system-wide studies. Our results demonstrated a unique portrait detailing alterations in angiogenesis and vascular integrity. Interestingly, only in-direct overlapped alterations between RNA and protein levels were detected, supporting the existence of multiple layers of regulation in CSC cascades. Notably, this is the first report identifying that both {beta}4 integrin and CAV1 signaling are downstream of CSC, conveying the angiogenic signaling. Our results provide a global view of signal transduction modulated by the CSC, identifies novel regulatory signaling networks and key cellular factors associated with CSC.

systems biology↗

bioRxiv2019

Changes in lipid composition and ultrastructure associated with functional maturation of the cuticle during adult maize leaf development

Although extensive prior work has characterized cuticle composition, function, ultrastructure and development in many plant species, much remains to be learned about how these features are interrelated. Moreover, very little is known about the adult maize leaf cuticle in spite of its significance for agronomically important traits in this major crop. We analyzed cuticle composition, ultrastructure, and permeability along the developmental gradient of partially expanded adult maize leaves to probe the relationships between these features. The water barrier property is acquired at the cessation of cell expansion. Wax types and chain lengths accumulate asynchronously along the developmental gradient, while overall wax load does not vary. Cutin begins to accumulate prior to establishment of the water barrier and continues thereafter. Ultrastructurally, pavement cell cuticles consist of an epicuticular layer, a thin cuticle proper that acquires an inner, osmiophilic layer during development, and no cuticular layer. Cuticular waxes of the adult maize leaf are dominated by alkanes and wax esters localized mainly in the epicuticular layer. Establishment of the water barrier coincides with a switch from alkanes to esters as the major wax type, and the emergence of an osmiophilic (likely cutin-rich) layer of the cuticle proper.\n\nHiglight statementChemical, ultrastructural and functional analysis of cuticle development in partially expanded adult maize leaves revealed important roles for wax esters and an osmiophilic, likely cutin-rich, layer in protection from dehydration.

plant biology↗