Biology subjects

Garcia-Munoz, A.

Publications and source records attributed to Garcia-Munoz, A..

12 recordsLinked to original sources

bioRxiv2025

Microenvironment-specific modulation of macrophage function and tumour progression by ADAMTS1 through Syndecan-4 shedding

Recent studies have emphasized the role of ADAMTS proteases in inflammation and immunity, particularly in the context of tumour progression. Since inflammatory cells can either constrain or promote tumour growth, understanding how ADAMTS proteases influence immune cell behaviour is crucial. Using syngeneic tumour models-B16F1 melanoma and Lewis Lung Carcinoma (LLC)-in Adamts1 knockout (Ats1-KO) mice, we observed model-specific outcomes underscoring the complexity of ADAMTS1 function in cancer. Transcriptomic and functional analyses revealed broad alterations in the matrisome and immune-related pathways across both tumour types. Strikingly, while tumour progression was impaired in B16F1-derived tumours, the LLC model-characterized by a stronger myeloid component-showed no dependency on Adamts1. To investigate this apparent resistance, we experimentally depleted macrophages and uncovered a profound functional defect in this population in Ats1-KO mice. In vitro assays confirmed reduced macrophage phagocytic activity. Mechanistically, we identified the transmembrane heparan sulfate proteoglycan syndecan-4 (SDC4), a known ADAMTS1 substrate, as a key mediator of this activity. Together, these findings reveal a previously unrecognized ADAMTS1-SDC4 axis that links extracellular matrix remodelling to macrophage phagocytosis, ultimately shaping tumour cell clearance and tumour progression.

cancer biology↗

bioRxiv2025

The effects of ploidy and mating system on the evolvability of populations: theoretical and empirical investigations

The amount of genetic diversity is a key parameter to understand the adaptive potential of populations. It has been demonstrated both theoretically and empirically that several factors influence genetic variance. In angiosperms, two of those are the ploidy level and the mating system of the populations. Polyploidy is theoretically known to increase adaptive potential in the long term. Self-fertilization has been theoretically associated with a decrease in genetic variance, even if it lacks empirical support. These factors have been studied independently, but are often shared in plants. However, there is a lack of empirical studies about the joint effects of polyploidy and selfing on genetic variance. In this paper, we conducted theoretical simulations to explore how genetic diversity could be affected by the ploidy level and mating system. We compared the simulation results with empirical estimates of genetic variance from the plant species Erysimum incanum, a selfing species from the Western Mediterranean basin exhibiting three different ploidy levels. We measured a series of phenotypic traits in individuals of each ploidy, obtained by controlled crosses and grown in different climatic conditions. While theoretical approaches showed a positive relationship between ploidy and genetic variance in both the short and long term, empirical results show lower evolvability and transgressive segregation for polyploids, both results being dependent on environmental conditions. Genetic variance in E. incanum polyploids could be related to recent establishment and adaptation to harsh environments, which explains the apparent contradiction with theory, where more settled and established populations are considered.

evolutionary biology↗

bioRxiv2025

Rapid adaptation and extinction across climates in synchronized outdoor evolution experiments of Arabidopsis thaliana

Climate change is threatening species with extinction, and rapid evolutionary adaptation may be their only option for population rescue over short ecological timescales. However, direct observations of rapid genetic adaptation and population dynamics across climates are rare across species. To fill this gap, we conducted a replicated, globally synchronized evolution experiment with the plant Arabidopsis thaliana for 5 years in over 30 outdoor experimental gardens with distinct climates across Europe, the Levant, and North America. We performed whole-genome sequencing on [~]70,000 surviving reproductive individuals and directly observed rapid and repeatable adaptation across climates. Allele frequency changes over time were parallel in experimental evolution replicates within the same climates, while they diverged across contrasting climates--with some allele frequency shifts best explained by strong selection between -46% to +60%. Screening the genome for signals of rapid climate adaptation identified a polygenic architecture with both known and novel adaptive genetic variants connected to important ecological phenotypes including environmental stress responses, CAM5 and HEAT SHOCK FACTORs, and germination and spring flowering timing, CYTOCHROME P450s and TSF. We found evolutionary adaptation trends were often predictable, but variable across environments. In warm climates, high evolutionary predictability was associated with population survival up to 5 years, while erratic trends were an early warning for population extinction. Together, these results show rapid climate adaptation may be possible, but understanding its limits across species will be key for biodiversity forecasting.

evolutionary biology↗

bioRxiv2025

Ploidy variation modulates outbreeding response and promotes mating system evolution in a selfing plant lineage.

O_LIOutbreeding response, the phenotypic differences observed between selfed parental lines and their outcrossed offspring, can influence the evolution of selfing strategies. However, such effect remains poorly understood in non-crop species. We investigated the phenotypic outbreeding response variation across ploidy levels in Erysimum incanum, a predominantly selfing plant complex with diploid, tetraploid, and hexaploid populations distributed across the Iberian Peninsula and Morocco. C_LIO_LIWe performed controlled within-population crosses to generate offspring with varying heterozygosity levels across ploidy types. We quantified individual, flower, and reproductive traits, and we estimated fitness components, and assessed trait modularity and phenotypic integration to see how heterozygosity affects trait coordination. C_LIO_LITetraploid showed the strongest and most consistently positive outbreeding responses, particularly in gamete production. Trait-specific outbreeding responses were positively associated with fitness across ploidy levels. Increasing heterozygosity was linked to a reduction in phenotypic integration, suggesting a loosening of trait correlations. C_LIO_LIOur results show that outbreeding response is ploidy-dependent and functionally connected to fitness. This suggests it may act as a selective force promoting outcrossing in highly inbred lineages. We suggest that outbreeding response is a dynamic and evolvable trait, with implications for mating system transitions and diversification in selfing plant populations. C_LI

plant biology↗

bioRxiv2024

Monitoring biodiversity in the global change era: The importance of herbaria and genetic diversity

Climate change is having far-reaching consequences on all living beings, altering ecosystems, habitats, and biodiversity worldwide. Species distributions are shifting or decreasing, with alpine plant species being particularly threatened. Natural population monitoring allows the assessment of the impact of human-induced global changes. However, traditional monitoring strategies based on individual counts may produce delayed signals of biodiversity loss. These approaches overlook the fact that genetic diversity is the fundamental basis for evolutionary processes, as it enables populations to adapt to environmental changes, including those caused by climate change. Here, we draw attention to the use of genetic diversity in monitoring schemes to anticipate negative trends in biodiversity and propose two fundamental methodologies: genomics and the use of herbarium specimens. Firstly, in contrast to genetic markers conventionally used to quantify genetic diversity, such as microsatellite markers, genomic approaches provide a vast amount of data that does not require previous knowledge of the studied organism, making them suitable for the study of non-model species. Secondly, herbaria worldwide serve as excellent sources of plant material for comparative studies across time with their precise chronologically recorded collection data. The accuracy of genetic diversity estimates increases with sample size, therefore a large number of vouchers is ideally required. However, the availability of specimens from the same species and populations in public herbaria is limited. Different strategies to quantify genetic diversity are proposed depending on the number of specimens available and their geographic distribution. Finally, we illustrate the potential of this approach in the most restrictive scenario, where only a few individuals are available, and there is no conspecific reference genome. Even in this restrictive scenario, there are signs of genetic depauperation in an alpine species with a narrow distribution, but not in a widely distributed congeneric.

plant biology↗

bioRxiv2024

Plant-animal below-ground interaction modifies plant phenotype and its above-ground interaction: a review and a new case study

Ecological interactions play a role in promoting and maintaining biodiversity. These interactions form complex networks of interconnected species. Therefore, changes resulting from an interaction in one of the partners can have indirect consequences on subsequent interactions with other species. Since the mutualism-antagonism continuum is a gradient, a shift in the strength and sign of an interaction is possible, highlighting the dynamic nature of interaction networks. In flowering plants, a wide variety of below- and above-ground interactions are established with a single host plant. Changes in the host, derived from such interactions, can modulate the outcome of the remaining connections in both strength and sign, and the overall configuration of the network. Thus, a species can mediate community-wide consequences through its interaction with the host by altering the plant phenotype. We present a case study where a root infection has unexpected consequences on the pollination host, driving phenotypic changes. This study provides new data on the dynamism of species interactions and the importance of obtaining a global view of interaction networks. Disentangling the direct and indirect effects of interactions and their impact on the rest of the interactions in wild communities is essential for a good understanding of the evolutionary and ecological mechanisms that promote and maintain biodiversity.

ecology↗

bioRxiv2023

Can changes in ploidy drive the evolution to allogamy in a selfing species complex?

O_LIThe evolution of mating systems in plants is central for understanding the rise of their diversity on Earth. The transition towards self-fertilization is a well-known example of convergent evolution although the opposite direction is expected to be forbidden according to evolutionary theories. We suggest that the ploidy level could promote changes in the reproductive strategies through its effect on traits related to pollination. C_LIO_LIWe performed controlled crosses on several populations from the polyploid Erysimum incanum species complex, described as predominantly selfing, to evaluate the inbreeding depression. Additionally, we measured mating traits such as floral size, herkogamy, anther exertion, the relative investment in male and female components (P:O ratio) and genetic diversity. C_LIO_LIWe described three ploidy levels in the complex - hexaploids were unknown until now. We found significant differences in the self-pollination success among ploidies and even among populations within the same ploidy. Inbreeding depression was present in higher ploidies, accompanied by bigger flowers with higher anther exposure, increased herkogamy and P:O and genetic diversity. C_LIO_LIThese findings suggest that ploidy could be promoting alternative reproductive strategies to selfing, driving mating system diversification within a selfing species, which has not been previously described in the wild. C_LI

plant biology↗

bioRxiv2023

Effects of ploidy and genetic diversity on competitive outcomes.

O_LIGenetic diversity affects evolutionary trajectories but their ultimate effects on ecological interactions and community dynamics remains poorly understood. It has been hypothesized that phenotypic novelties produced by ploidy and heterozygosity modify the ecological interactions between novel genotypes and more ancient locally adapted ones, and therefore, their opportunities to coexist. C_LIO_LIWe performed a greenhouse competition experiment with three taxa of the Erysimum incanum species complex differing in ploidy (2x, 4x and 6x) and heterozygosity (high and low). This experiment allows us to parameterize a population model to test the effect of genetic diversity on modulating the ecological forces that determine the outcome of competition, niche and fitness differences. C_LIO_LIDepending on whether ploidy variation and the level of heterozygosity made interspecific competition greater or smaller than intraspecific competition, we predicted either priority effects or coexistence. Such competitive outcome differences were explained by the phenotypic expression in the number of stalks (plant size surrogate) with genotypes under priority effects showing more stalks. C_LIO_LIAltogether, our results show that non-polyploid plants can coexist with polyploids contravening theoretical expectations of polyploidy dominance under stable conditions. However, historical contingency such as order of arrival promotes priority effects when adaptive phenotypic optimums strongly compete for space. C_LI

ecology↗

bioRxiv2022

Ploidy effects on the relationship between floral phenotype, reproductive investment and fitness exhibited by an autogamous species complex

PremiseThe relationships between reproductive investment, phenotype and fitness have been broadly studied in cross-pollinated plants in contrast to selfing species, which are considered less interesting in this area because they are supposed to be a dead-end in any evolutionary pathway. Still, selfing plants are unique systems to study these questions since the position of reproductive structures and traits related to flower size play an important role in female and male pollination success. MethodErysimum incanum s.l. is a selfing species complex exhibiting three levels of ploidy: diploids, tetraploids and hexaploids. This species complex shows traits typically associated with the selfing syndrome. Here, we used 1609 plants belonging to these three ploidies to characterize floral phenotype and spatial configuration of reproductive structures, reproductive investment (pollen and ovules production) and plant fitness. Then, we explored the relationship between all these variables using structural equation modelling across ploidy levels. Key ResultsAn increase in ploidy level leads to bigger flowers with more exerted stamens and a greater amount of pollen and ovules. In addition, hexaploid plants exhibit higher absolute values for herkogamy which is positively correlated with fitness. Phenotypic traits and pollen production are indirectly selected by the relationship among ovules and fitness, maintained across ploidies. ConclusionsChanges in floral phenotypes, reproductive investment and fitness with the ploidy level suggests that genome duplication can be a driver for the reproductive strategy transitions by modifying the investment in pollen and ovules and linking them with plant phenotype and fitness.

evolutionary biology↗

bioRxiv2021

Ruminant-associated Listeria monocytogenes isolates belong preferentially to dairy-related hypervirulent clones: a longitudinal study in 19 farms

The increasing prevalence of Listeria monocytogenes infections is a public health issue. Although studies have shown that ruminants constitute reservoirs of this foodborne pathogen, little is known about its epidemiology and genetic diversity within ruminant farms. Here we conducted a large-scale genomic and epidemiologic longitudinal study of Listeria spp. in dairy ruminants and their environments, comprising 19 farms monitored for three consecutive seasons (N=3251 samples). L. innocua was the most prevalent Listeria spp, followed by L. monocytogenes. L. monocytogenes was detected in 52.6% of farms (prevalence in feces samples 3.8%, in farm environment samples 2.5%) and more frequently in cattle (4.1%) and sheep (4.5%) than in goat farms (0.2%). Lineage I accounted for 69% of L. monocytogenes isolates. Among animal samples, the most prevalent sublineages (SL) and clonal complexes (CC) were SL1/CC1, SL219/CC4, SL26/CC26 and SL87/CC87, whereas SL666/CC666 was prevalent in environmental samples. 61 different L. monocytogenes CTs (cgMLST sequence types) were found, 17 of them (27.9%) common to different animals and/or surfaces within the same farms. L. monocytogenes prevalence was not affected by farm hygiene but by season: the overall prevalence of L. monocytogenes in cattle farms was higher during winter, and in sheep farms was higher during winter and spring. Cows in their second lactation had a higher probability of L. monocytogenes fecal shedding than other lactating cows. This study highlights that dairy farms constitute a reservoir for hypervirulent L. monocytogenes and the importance of continuous animal surveillance to reduce the burden of human listeriosis. IMPORTANCEListeria monocytogenes is a bacterial pathogen responsible for listeriosis, the foodborne disease with the highest hospitalization and case-fatality rate. Despite increasing evidence that dairy products and ruminant farms are important reservoirs of L. monocytogenes, little is known about the epidemiology and genetic diversity of Listeria spp. within dairy ruminant farms. We report the largest Listeria spp. longitudinal study in individual domestic animals, and the first using whole-genome sequencing for a deep isolate characterization. Here, we show that domestic ruminants can be asymptomatic carriers of pathogenic Listeria, that L. monocytogenes fecal shedding is often intermittent, and that hypervirulent L. monocytogenes clones are overrepresented in dairy farms. Moreover, we uncover the effect of seasons and lactation number on the prevalence of L. monocytogenes in ruminants. Our study highlights the need for Listeria spp. monitoring in farm animals to control the spread of hypervirulent L. monocytogenes and reduce the burden of human listeriosis.

microbiology↗

bioRxiv2019

A Synergistic Anti-Cancer FAK and HDAC Inhibitor Combination Discovered by a Novel Chemical-Genetic High Content Phenotypic Screen

We mutated the Focal Adhesion Kinase (FAK) catalytic domain to inhibit binding of the chaperone, Cdc37 and ATP, mimicking the actions of a FAK kinase inhibitor. We re-expressed mutant and wild-type FAK in squamous cell carcinoma (SCC) cells from which endogenous FAK had been deleted, genetically fixing one axis of a FAK inhibitor combination high-content phenotypic screen to discover drugs that may synergize with FAK inhibitors. HDAC inhibitors represented the major class of compounds that potently induced multi-parametric phenotypic changes when FAK was rendered kinase-defective, or inhibited pharmacologically in SCC cells. Indeed, combined FAK and HDAC inhibitors arrest proliferation and induce apoptosis in a sub-set of cancer cell lines in vitro and efficiently inhibits tumor growth in vivo. Mechanistically, HDAC inhibitors potentiate inhibitor-induced FAK inactivation and reverses FAK-associated nuclear YAP in sensitive cancer cell lines. Here we report the discovery of a new clinically actionable synergistic combination between FAK and HDAC inhibitors.\n\nSignificanceWe describe a chemical-genetic, high-content phenotypic screening approach to discover effective anti-cancer combinations of targeted therapeutics through which we identified a novel, synergistic and clinically actionable, combination of FAK and HDAC inhibitors.

cancer biology↗

bioRxiv2017

ZMYND10 functions in a chaperone relay during axonemal dynein assembly

Molecular chaperones promote the folding and macromolecular assembly of a diverse set of substrate client proteins. How the ubiquitous chaperone machinery directs its activities towards a specific set of substrates and whether this selectivity could be targeted for therapeutic intervention is of intense research. Through the use of mouse genetics, imaging and quantitative proteomics we uncover that ZMYND10 is a novel co-chaperone for the FKBP8-HSP90 chaperone complex during the biosynthesis of axonemal dynein heavy chains required for cilia motility. In the absence of ZMYND10, defects in dynein heavy chains trigger broader dynein motor degradation. We show that FKBP8 inhibition phenocopies dynein motor instability in airway cells, and human disease-causing variants of ZMYND10 disrupt its ability to act as FKBP8-HSP90 co-chaperone. Our study indicates that the motile ciliopathy Primary Ciliary Dyskinesia (PCD) should be considered a cell-type specific protein-misfolding disease and opens the potential for rational drug design that could restore specificity to the ubiquitous chaperone apparatus towards dynein subunits.

cell biology↗