Biology subjects

Rodriguez, M. A.

Publications and source records attributed to Rodriguez, M. A..

9 recordsLinked to original sources

bioRxiv2026

Establishment of a patient-derived adrenocortical carcinoma 3D tumor construct platform for evaluation of therapeutic strategies

Adrenocortical carcinoma (ACC) is an under-studied, aggressive cancer of the adrenal glands where surgical resection is currently the only effective curative option. However, after surgery the majority of patients experience tumor progression. The median overall survival of 12 months has not improved since approval of mitotane in 1970. The lack of effective therapies in ACC is partially due to the lack of preclinical models that accurately represent human ACC. Most attempts to generate ACC cell lines or animal models have been unsuccessful. The few existing models do not adequately reflect the oncogenic signaling pathways or intratumoral heterogeneity of human ACC. These limited model systems have hindered identification of drivers of tumor progression and immune escape mechanisms, thereby limiting development and testing of novel therapeutic approaches such as targeted therapies or immunotherapies. We developed human ACC patient-derived tumor constructs (PTCs) encapsulated in synthetic extracellular matrix. Our ACC PTCs exhibit hallmarks of ACC: proliferation, expression of key ACC biomarkers, such as SF1, and production of cortisol. We provide characterization in the form of immunofluorescence staining for ACC biomarkers, and confirmation of PTC proliferation and cortisol production - a hallmark of ACC. We then demonstrate the utility of ACC PTCs for evaluation of chemotherapies currently used clinically (mitotane) with and without experimental cocktails of etoposide, doxorubicin, and cisplatin, experimental targeted therapies, and cellular immunotherapies, primarily in the form of natural killer (NK) cell therapy. In particular, the latter - cellular immunotherapies - are cutting edge studies demonstrating potential to evaluate immunotherapies in ACC clinical scenarios. Together these data provide evidence that patient-derived ACC models can serve as an important tool for identification of future points of intervention and testing of novel therapeutic strategies to improve ACC clinical care.

cancer biology↗

bioRxiv2025

sabinaHSBM: An R package for link prediction network reconstruction using Hierarchical Stochastic Block Models

O_LINetwork analysis is a powerful framework for investigating complex systems across disciplines, including ecology, where it helps uncover patterns in predator-prey, host- parasite, or plant-pollinator interactions. However, ecological network data are often incomplete or error-prone due to sampling limitations, detection failures, and taxonomic uncertainty--leading to missing (false negative) and spurious (false positive) links that obscure structure and hinder inference. The hierarchical stochastic block model (HSBM), particularly in its degree-corrected form, is among the most effective tools for reconstructing networks under such uncertainty. Despite its robustness, the primary implementation of HSBM in the Python-based graph-tool library has remained largely inaccessible to ecologists. C_LIO_LIHere, we introduce sabinaHSBM, the first R package that makes degree-corrected HSBM broadly available through a user-friendly, flexible workflow. By bridging a gap between advanced network modeling and widely used ecological analysis platforms, sabinaHSBM facilitates network reconstruction and link prediction from binary bipartite data. The workflow involves three main steps: (1) preparing input data, (2) estimating posterior link probabilities, and (3) reconstructing the network. The package supports detection of undocumented and spurious links, exploration of hierarchical structure, and propagation of uncertainty throughout. Key features include cross-validation, flexible thresholding, probabilistic evaluation metrics, and two link prediction modes: estimating all link probabilities or identifying undocumented ones. C_LIO_LIWe illustrate the packages functionality through a case study using a published global dataset of carnivore-parasite associations, showing that inferred groupings are phylogenetically clustered. To assess predictive accuracy, we examined the top 10 highest-probability links identified by the model and found published evidence for 8, despite their absence from the original dataset. This highlights the models ability to recover biologically meaningful but underreported interactions. C_LIO_LIBy integrating all components of HSBM-based reconstruction into an accessible R package, sabinaHSBM empowers researchers to improve relational data quality and uncover overlooked patterns in complex ecological networks and beyond. C_LI

ecology↗

bioRxiv2025

Fibroblasts drive differential response in immunotherapy via IL-6 in bioengineered 3D cancer constructs

Despite various therapeutic advancements in cancer, heterogeneity in the tumor microenvironment is a major hindrance to the overall efficacy of treatment. In this study, we focus on the most abundantly found cellular stromal components - fibroblasts - which can be tumor-promoting or tumor-suppressing based on the extent of disease progression and numerous additional factors. In the studies described herein, we evaluated their role in influencing chemotherapy as well as in immunotherapy using colorectal cancer (CRC) cell line-derived 3D tumor constructs. Our initial efforts centered on common chemotherapeutic agents utilized in CRC. However, while the presence of fibroblasts often did influence chemotherapy efficacy, a clear and consistent increase or decrease in efficacy was not obvious. We then focused subsequent studies on natural killer (NK) cell-based immunotherapy efficacy. There are numerous components and pathways involved in tumorigenesis and tumor-immune cell interactions, and the crosstalk between fibroblasts and immune cells like NK cells is still not well-defined. Fibroblasts have been documented to be a major player with respect to immune modulation and understanding this in greater detail can elucidate more options for anti-tumor immunity. Specifically, we used an extracellular matrix-based hydrogel platform to generate 3D CRC constructs to evaluate how fibroblasts affect tumor cell viability in presence and absence of NK cells. In general, fibroblasts aid the tumor cells in our models. We then identify a cytokine-based pathway (interleukin 6 [IL-6]) via which activated fibroblasts engage with the tumor cells and show how NK cell effector function can be restored when the IL-6 pathway is blocked in a melanoma-based tumor-on-a-chip platform. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/660473v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@53797forg.highwire.dtl.DTLVardef@4dbc83org.highwire.dtl.DTLVardef@19346deorg.highwire.dtl.DTLVardef@11d834_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Bioregionalization: From Wallace and Humboldt to deep-time paleoregion dynamics

Bioregionalization methods allow us to classify and map biogeographic units using data on species composition and traits. Here, we reviewed the evolution of the field during the last 70 years, seeking to summarize its history, and identify gaps and future avenues for research. Our results show that the aim of the studies using bioregionalization methods changed in time. First, bioregionalization were used to unveil the drivers of the observed spatial patterns of biodiversity on Earth, and to understand the role of dispersal limitations on the evolutionary history of clades, but recently, these methods are mostly used for conservation management. Further, data used to map biodiversity regions, the ones that we are now defining conservation strategies, are taxonomically and geographically biased, with a large percentage of the papers using vertebrate data from developed continents/countries. Finally, we show how key papers in the field, the ones with most citations, heavily depend on expert criteria and non-reproducible workflows, preventing direct comparison of maps of bioregions from different papers. Following our findings, we identified 3 gaps for the advance in the field, 1) We need to move beyond maps of vertebrate composition. Ideally, we need to increase the taxonomic diversity of the studies, but also to add other type of information, like data on species traits, genetic diversity, or phylogenetic distances. 2) we need reproducible and standardized methods 3) we need to further explore the temporal dimension of bioregions, to understand how they evolved through time.

ecology↗

bioRxiv2023

A 3D adrenocortical carcinoma tumor platform for preclinical modeling of drug response and matrix metalloproteinase activity

Adrenocortical carcinoma (ACC) has a poor prognosis, and no new drugs have been identified in decades. The absence of drug development can partly be attributed to a lack of preclinical models. Both animal models and 2D cell cultures of ACC fail to accurately mimic the disease, as animal physiology is inherently different than humans, and 2D cultures fail to represent the crucial 3D architecture. Organoids and other small 3D in vitro models of tissues or tumors can model certain complexities of human in vivo biology; however, this technology has largely yet to be applied to ACC. In this study, we describe the generation of 3D tumor constructs from an established ACC cell line, NCI-H295R. NCI-H295R cells were encapsulated to generate 3D ACC constructs. Tumor constructs were assessed for biomarker expression, viability, proliferation, and cortisol production. In addition, matrix metalloproteinase (MMP) functionality was assessed directly using fluorogenic MMP-sensitive biosensors and through infusion of NCI-H295R cells into a metastasis-on-a-chip microfluidic device platform. ACC tumor constructs showed expression of biomarkers associated with ACC, including SF-1, Melan A, and inhibin . Treatment of ACC tumor constructs with chemotherapeutics demonstrated decreased drug sensitivity compared to 2D cell culture. Since most tumor cells migrate through tissue using MMPs to break down extracellular matrix, we validated the utility of ACC tumor constructs by integrating fluorogenic MMP-sensitive peptide biosensors within the tumor constructs. Lastly, in our metastasis-on-a-chip device, NCI-H295R cells successfully engrafted in a downstream lung cell line-based construct, but invasion distance into the lung construct was decreased by MMP inhibition. These studies, which would not be possible using 2D cell cultures, demonstrated that NCI-H295R cells secreted active MMPs that are used for invasion in 3D. This work represents the first evidence of a 3D tumor constructs platform for ACC that can be deployed for future mechanistic studies as well as development of new targets for intervention and therapies. SignificanceThe paucity of preclinical research models has contributed to lack of progress in treatment of adrenocortical carcinoma (ACC). Three-dimensional modeling of ACC may provide novel insights for preclinical studies and advance ACC research.

cancer biology↗

bioRxiv2022

Significant phylogenetic signal is not enough to trust phylogenetic predictions

In a recent study, Cantwell-Jones et al. (2022) proposed a list of 1044 species as promising key sources of B vitamins based primarily on phylogenetic predictions. To identify candidate plants, they fitted lambda models of evolution to edible species with known values in each of six B vitamins (232 to 280 species) and used the estimated parameters to predict B-vitamin profiles of edible plants lacking nutritional data (6460 to 6508 species). The latter species were defined as potential sources of a B vitamin if the predicted vitamin content was [≥]15% towards recommended dietary allowances for active females between 31-50 years per 100 g of fresh edible plant material consumed. Unfortunately, the reliability of the predictions that informed the list of candidate species is questionable due to insufficient phylogenetic signal in the data (Pagels {lambda} between 0.171 and 0.665) and a high incidence of species with missing values (over 95% of all the species analyzed in the study). We found that of the 1044 species proposed as promising B-vitamin sources, 626 to 993 species showed accuracies that were indistinguishable from those obtained under a white noise model of evolution (i.e. random predictions conducted in absence of any phylogenetic structure) in at least one of the vitamins, which proves the weakness of the inference drawn from imputed information in the original study. We hope this commentary serves as a cautionary note for future phylogenetic imputation exercises to carefully assess whether the data meet the requirements for the predictions to be valuable, or at least more accurate than expected by chance.

evolutionary biology↗

bioRxiv2021

Scaling up: understanding movement from individual differences to population-level dispersal

Dispersal is fundamental to life on our planet. Dispersal facilitates colonization of continents and islands. Dispersal mediates gene flow among populations, and influences the rate of spread of invasive species. Theory suggests that individuals consistently differ in dispersal propensity, however determining the relative contributions of environmental factors to individual and population-level dispersal, represent a major challenge to understand the spread of organisms. To address this, we conducted a field experiment using Drosophila melanogaster. As proxies for individuals with different dispersal propensities, we used wildtype strains of flies with natural variants of the foraging gene, known to influence dispersal in laboratory and field experiments. These included flies with fors alleles known to be less dispersive, flies with the forR alleles which are more dispersive flies as well as an outbred population established from field collected flies. We released approximately 6000 flies of each strain in an experimental arena (100 m x 100 m) in the field and our recaptures were used to determine dispersal of flies over time. To estimate environmental effects on dispersal, we measured temperature, wind direction and wind speed. Using partial-differential equations we combined ecological diffusion with advection to estimate dispersal rates and responses to wind. We found that temperature effects elicited a similar response in high and low dispersal lab strains with dispersal rate increasing with temperature most rapidly at temperatures above 18{degrees}C. This was in contrast to outbred flies which remained unresponsive to temperature changes. We also detected a response to wind with advection rates increasing linearly with wind speed for all flies in general. Our results suggest that response to temperature and wind can minimize known differences in behavioural predispositions to disperse. Our results also suggest that the direction and magnitude of wind may play a key role in the colonization and distribution of fly populations. Our findings therefore have implications for forecasting the spread of pests and invasive species as well as pathogens and vectors of disease. Our findings further contribute to the understanding of how the environment can modify behavioural predispositions and to influence population-level dispersal in fly populations in particular and insect species in general.

ecology↗

bioRxiv2019

Characterization of neurogenic niches in the telencephalon of juvenile and adult sharks

Neurogenesis is a multistep process by which progenitor cells become terminally differentiated neurons. Adult neurogenesis has gathered increasing interest with the aim of developing new cell-based treatments for neurodegenerative diseases in humans. Active sites of adult neurogenesis exist from fish to mammals, although in the adult mammalian brain the number and extension of neurogenic areas is considerably reduced in comparison to non-mammalian vertebrates, and they become mostly reduced to the telencephalon. Much of our understanding in this field is based in studies on mammals and zebrafish, a modern bony fish. The use of the cartilaginous fish Scyliorhinus canicula (representative of basal gnathostomes) as a model expands the comparative framework to a species that shows highly neurogenic activity in the adult brain. In this work, we studied the proliferation pattern in the telencephalon of juvenile and adult specimens of S. canicula by using antibodies against the proliferation marker PCNA. We have characterized proliferating niches by using stem cell markers (Sox2), glial markers (GFAP, BLBP and GS), intermediate progenitor cell markers (Dlx2 and Tbr2) and markers for migrating neuroblasts (DCX). Based in the expression pattern of these markers, we demonstrate the existence of different cell subtypes within the PCNA immunoreactive zones including non-glial stem cells, glial progenitors, intermediate progenitor-like cells and migratory neuroblasts, which were widely distributed in the ventricular zone of the pallium, suggesting that the main progenitor types that constitute the neurogenic niche in mammals are already present in cartilaginous fishes.

neuroscience↗

bioRxiv2017

Pleistocene climate change and the formation of regional species pools

This preprint has been reviewed and recommended by Peer Community In Evolutionary Biology (https://doi.org/10.24072/pci.evolbiol.100053). Despite the description of bioregions dates back from the origin of biogeography, the processes originating their associated species pools have been seldom studied. Ancient historical events are thought to play a fundamental role in configuring bioregions, but the effects of more recent events on these regional biotas are largely unknown. We use a network approach to identify regional and sub-regional faunas of European Carabus beetles, and analyse the effects of dispersal barriers, niche similarities and phylogenetic history on their configuration. We identify a transition zone matching the limit of the ice sheets at Last Glacial Maximum. While southern species pools are mostly separated by dispersal barriers, in the north species are mainly sorted by their environmental niches. Strikingly, most phylogenetic structuration of Carabus faunas occurred during the Pleistocene. Our results show how extreme recent historical events -such as Pleistocene climate cooling, rather than just deep-time evolutionary processes, can profoundly modify the composition and structure of geographic species pools.

ecology↗