Biology subjects

Sanchez, L.

Publications and source records attributed to Sanchez, L..

At least 19 recordsLinked to original sources

bioRxiv2026

SIM2s coordinates programmed mitophagy with respiratory chain supercomplex remodeling during mammary epithelial differentiation

Lactation requires mammary epithelial cells (MECs) to rapidly expand mitochondrial function while remodeling the mitochondrial population that supports milk synthesis and secretion. Programmed mitophagy is required for MEC differentiation, yet why mitochondrial turnover is necessary during this developmental transition remains poorly understood. Using Mito-QC reporter mice, we identified developmentally regulated changes in mitolysosome burden across the transition from late pregnancy to lactation that were altered by mammary-specific gain or loss of the bhlh/PAS protein, SIM2s (single-minded 2 s). In differentiating HC11 cells, mitochondrial turnover was accompanied by increased assembly and activity of respiratory supercomplexes containing complexes I, III, and IV. Depletion of PRKN prevented acquisition of this differentiation-associated respiratory profile and impaired lactogenic differentiation. SIM2s co-migrated with higher-order respiratory assemblies, and loss of SIM2s reduced supercomplex assembly and activity in HC11 cells and mammary tissue. SIM2s also localized in close proximity to complex III in differentiated mammary epithelium, whereas loss of SIM2s reduced proximity between complexes III and IV. Together, these findings support a model in which SIM2s coordinates PRKN-dependent mitochondrial turnover with respiratory-chain remodeling during MEC differentiation. Our results suggest that programmed mitophagy does more than remove mitochondria during development; it contributes to establishment of a mitochondrial population with a respiratory-chain architecture suited to the emerging differentiated state.

cell biology↗

bioRxiv2026

Supplemental irrigation during heat waves affects yield but not whole-vine carbohydrates in wine grapes

As extreme heat events increase in frequency and intensity worldwide, understanding how woody perennial crops respond to higher maximum temperatures is critical. Perennials face distinct challenges, persisting across many seasons under increasingly variable and extreme conditions, and heat waves threaten the viability of wine grape cultivars through impacts on yield, wine quality, and long-term vine health. To test whether irrigation practices before and during heat waves affect grapevine carbon (C) storage and health, we experimentally manipulated irrigation regimes surrounding heat waves from 2019-2021 in a commercial Cabernet Sauvignon vineyard in the Lodi AVA of Californias Central Valley. Vine physiological traits and yield were measured throughout, and whole-vine nonstructural carbohydrate (NSC) concentrations were quantified after three growing seasons. Although lower supplemental irrigation reduced photosynthesis, stomatal conductance, and fruit yield, whole-vine NSCs did not differ significantly in any perennial organ by the experiments end, indicating that reproductive output and final NSC status responded to irrigation on different timescales. These results suggest that moderate supplemental irrigation during heat events is sufficient to mitigate negative impacts on yield and quality while supporting recovery of NSC reserves, though longer-term monitoring is needed to confirm that this short-term resilience persists.

Plant Biology↗

bioRxiv2026

Enhanced Irrigation during Extreme Heat Events Preserves Anthocyanins in Cabernet Sauvignon

Globally, heat waves (HWs) have become more frequent, intense, and prolonged, with extreme temperatures that reduce quality or result in crop loss in wine grapes. Irrigation prior to or during HWs is one of the most common means of mitigating damage to vines and berries. However, the effect of this practice on flavonoids is not well established. Red wine quality is directly impacted by phenolics, including anthocyanins and proanthocyanidins (PAs). This study was conducted over three vintages (2019-2021) in a commercial vineyard to evaluate the impact of supplemental irrigation - applied before and during HWs - on winegrape chemistry in Cabernet Sauvignon. Results demonstrated that supplemental irrigation significantly reduced anthocyanin loss compared to a control treatment maintained at 60% evapotranspiration (ET), and that pre-HW irrigation can mitigate some of the deleterious effects on classes of flavonoids important to red wine quality. Furthermore, applying excessive water (3x, or 180% ET) had no additional beneficial effects on flavonoids relative to a moderate supplemental application (2x, or 120% ET).

biochemistry↗

bioRxiv2026

Acute hypoxia induces transient olfactory dysfunction through olfactory epithelial degeneration and bulbar mitochondrial stress in zebrafish

Hypoxic-ischemic injury is a major cause of olfactory dysfunction, yet the cellular and morphological mechanisms underlying this sensory loss remain poorly understood. Here, we investigated the structural, cellular, and functional effects of acute hypoxic exposure on the olfactory system of adult zebrafish (Danio rerio) of both sexes, a model organism with remarkable neuroregenerative capacity. Fish were subjected to 15 minutes of acute severe hypoxia (0.8 mg/L dissolved oxygen) and assessed at 1 and 5 days post-hypoxia (dph). We evaluated olfactory function by means of cadaverine-evoked aversive behavioral assays. Structural and morphological integrity and inflammation of the olfactory epithelium (OE) and olfactory bulb (OB) were characterized using immunohistochemistry, histological stainings, and a 2,3,5-triphenyltetrazolium chloride (TTC) colorimetric assay. Acute hypoxic exposure impaired olfactory-mediated behaviors without affecting locomotion or exploratory behavior. In the peripheral OE, hypoxia caused neurodegeneration, disruption of the nasal mucus layer, and robust leukocytic infiltration. We observed reduced mitochondrial dehydrogenase activity in the olfactory bulb (OB) along with reactive astrogliosis. Olfactory function recovered by 5 days, coinciding with full restoration of OE morphology, and supported by a strong proliferative response. These findings reveal a coordinated degenerative and regenerative response to hypoxia across the olfactory axis, with implications for understanding hypoxia-induced sensory loss and neural repair. SIGNIFICANCEThis work addresses an important gap in knowledge regarding the mechanisms linking hypoxic insult and olfactory dysfunction. By using adult zebrafish, an extraordinarily regenerative vertebrate, it also provides insight into neuronal repair and regenerative processes supporting olfactory recovery. The novelty of our study resides in that, to our knowledge, there are no studies that provide a comprehensive characterization of the effects of hypoxia in the olfactory system across molecular, histological, and functional levels. These findings advance our understanding of hypoxia-induced sensory neurodegeneration and regeneration, and highlight the zebrafish olfactory system as a powerful model for investigating neural repair mechanisms relevant to hypoxic-ischemic brain injury.

neuroscience↗

bioRxiv2026

Development of the 4TREE SNP array, a forest multispecies array to enhance European Breeding and conservation programs in pine, poplar and ash.

Within the framework of the European Adaptive BREEDING for Better FORESTs project (B4EST, https://b4est.eu/), we have developed genotyping tools for Poplar, Ash, and Pine forest tree species. SNP arrays are attractive genotyping tools because of the user-friendly genotype calling system and the robust transferability among laboratories. Here we describe the development of an Axiom SNP array for Pinus pinaster (13,407 SNPs), Pinus pinea (5,671 SNPs), Poplar spp. (13,408 SNPs), and Fraxinus spp. (13,407 SNPs) based on a two-step process. We first assembled a high-density (>100,000 SNPs/species) screening array that served to test a large panel of candidate SNPs on a diversity panel involving at least 120 individual trees per species or species group. In the second step, we selected and combined the most informative SNPs to build the final 50,000 SNP 4TREE array. This approach resulted in high genotyping success rates, including for species lacking previously validated high-quality SNP resources. The 4TREE SNP array provides a valuable and transferable genomic tool to support genomic prediction, breeding, and adaptive management of forest tree species.

genomics↗

bioRxiv2026

Tensile Expansion Microscopy Applies Mechanical Force to Super-resolve Fixed and Image Live Cellular Samples

Understanding biophysical phenomena requires techniques that access biologically relevant spatial and temporal scales. Expansion Microscopy (ExM) is a sample preparation approach which achieves super-resolution spatial scales by leveraging osmotic forces in a swellable hydrogel to physically separate structures to distances larger than the diffraction limit of light. Yet, in traditional osmotic ExM only pre- and post- expanded samples can be imaged. Further, fragmentation, hydrogel deformation, and signal loss are common while requiring samples to be chemically fixed. Therefore, there is little control of the expansion, reproducibility can be challenging, and dynamics of biological samples at applicable temporal scales cannot be observed. Here, we develop Tensile Expansion Microscopy (TExM) to mechanically expand fixed and, notably, living cellular samples. Highly-stretchable and tough double network alginate- Ca2+/polyacrylamide hydrogels are expanded by tensile forces applied using an electromechanical iris expansion device during continuous imaging on a fluorescence microscope. We incorporate two-photon polymerized microscale fluorescent fiducial markers to track samples and distortion during expansion. The hydrogels controllably and repeatedly expand up to 3.3x with distortions less than 12 {micro}m across 1.3 mm2. TExM is first applied to fixed NIH 3T3 fibroblast cells with immunohistochemistry-stained microtubules, achieving super-resolutions of 100 nm. Then, TExM is demonstrated with living HeLa cells with internal fluorescent reporters showing increased cell size and cell-to-cell separation under 3.2x linear expansion. Overall, TExM allows for continuous, stepwise, and precise temporal modulation of lateral substrate strain, enabling real time monitoring of dynamics of both fixed and viable live cell processes at higher spatial resolutions. TExM can further investigate broad biophysical questions due to its compatibility with other analytical imaging methods that are sensitive to water or fixatives used in traditional osmotic ExM.

biophysics↗

bioRxiv2026

Optimizing irrigation during heat events sustains grapevine physiology and fruit production

O_LIIncreasing frequency, intensity, and duration of heat waves (HWs) threaten agricultural production globally by constraining physiological function and fruit production. Supplemental irrigation mitigates heat stress in grapevine and other woody perennial crops, yet water scarcity necessitates optimized irrigation strategies during extreme heat. C_LIO_LIWe conducted a three-year field trial in a commercial Cabernet Sauvignon vineyard, applying differential irrigation only before and during naturally occurring HWs: baseline (50% ET), moderate (90-120% ET), and high (120-180% ET). We monitored water potentials, leaf gas exchange, canopy temperature, yield, and berry composition. C_LIO_LIBaseline irrigation consistently reduced net photosynthesis, stomatal conductance, and leaf cooling capacity during HWs. Moderate supplemental irrigation maintained gas exchange, transpiration, and leaf temperature, mitigating yield losses. Excessive irrigation beyond moderate levels provided no additional physiological benefit and decreased crop water use efficiency and berry quality. C_LIO_LIOur results demonstrate that targeted, event-based irrigation sustains grapevine physiological performance and fruit production under extreme heat, whereas both insufficient and excessive water negatively affect carbon assimilation, stomatal regulation, and crop productivity. These findings emphasize the importance of aligning water management with heat event timing to preserve vine function, optimize water use, and maintain yield and fruit quality in water-limited regions. C_LI

plant biology↗

bioRxiv2026

Population structure of Phytophthora infestans collected from potatoes in Ecuador, Colombia, Peru, Bolivia and Uruguay

Late blight, a destructive disease affecting potatoes, is caused by the oomycete Phytophthora infestans and remains a major threat to potato production worldwide. Understanding the population structure of this pathogen is essential for effective disease management. We examined the genetic structure of South American P. infestans populations using 182 isolates: 97 from Bolivia and southern Peru, 14 from Colombia, 57 from Ecuador (1993-2022), and 14 from Uruguay. The isolates were characterized by clonal lineage, mitochondrial haplotype, and mating type using multilocus genotypes based on microsatellite (SSR) markers. In Bolivia, only the lineage/haplotype 2A1/Ia was identified, whereas Peru exhibited both 2A1/Ia and EC1/IIa, all of which were mating type A1. Puno was the sole department where both lineages were present. In historical Ecuadorian populations, we found US1/Ib and EC1/IIa (P. infestans), as well as EC2/Ic and EC3/Ia (Phytophthora andina), while recent populations showed only US1. In Colombia, EC1/IIa and a distinct clonal lineage (CO4/Ia) were identified within the present dataset. In Uruguay, 2A1/Ia was predominant. These results provide updated insights into the genetic diversity and geographic distribution of P. infestans across South America and highlight the importance of continued regional surveillance for improved late blight management.

plant biology↗

bioRxiv2025

Critical role of Cas9 aggregation on in vitro DNA cleavage

The CRISPR/Cas9 system is a powerful genome-editing tool widely used in molecular biology and gene therapy, whose efficiency strongly depends on the physicochemical properties of the Cas9 ribonucleoprotein complex. Optimizing Cas9 activity remains essential for reliable genome- editing applications, yet the factors limiting its in vitro cleavage efficiency are not fully understood. Among these, protein aggregation has been suggested to critically impair Cas9 functionality, although its role has not been systematically analysed. Here, we investigate Cas9 aggregation under different environmental conditions and evaluate its impact on in vitro DNA cleavage efficiency. Using fluorescently labelled Cas9 and single-molecule fluorescence techniques, we quantify aggregation as a function of buffer composition, ionic strength, salt concentration and sgRNA presence, and relate these properties to cleavage activity. Our results show that Cas9 aggregation significantly reduces DNA cleavage efficiency, with higher aggregation levels consistently correlating with lower activity. In contrast, buffers with higher ionic strength or stabilizing components reduce aggregation and enhance Cas9 performance. Overall, this study demonstrates that Cas9 aggregation plays a critical role in determining in vitro cleavage efficiency and highlights the importance of controlling protein aggregation to optimize CRISPR/Cas9-based genome-editing applications and delivery strategies. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=73 SRC="FIGDIR/small/696176v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@14dbd87org.highwire.dtl.DTLVardef@d5f812org.highwire.dtl.DTLVardef@1916c53org.highwire.dtl.DTLVardef@5ed798_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

HDL-associated phosphatidylserine blunts myeloid activation and protects from atherosclerosis

Background and aimsLipids play a critical role in atherosclerosis. Low-density lipoprotein (LDL)-cholesterol and certain lipid classes like sphingomyelins are associated with inflammation and poor cardiovascular outcomes. Phosphatidylserine (PS), on the other hand, is a negatively charged anti-inflammatory phospholipid class involved in efferocytosis. In this study, we sought to investigate its anti-atherosclerotic properties through a combination of complementary human lipidomics analyses, in vitro assays and in vivo experiments in Apoe-/- mice. MethodsHuman lipidomics studies were performed on the 300OB cohort comprising 300 obese and overweight individuals at risk of cardiovascular disease. In vitro assays were carried out using human monocytes and macrophages, and in vivo experiments included histopathological, immunophenotyping and single-cell transcriptomic analyses. ResultsIn humans, we identified PS as an anti-inflammatory and atheroprotective biomarker. Hence, we developed a high-density lipoprotein (HDL)-like formulation enriched in PS to exploit its properties in a targeted fashion in mice. In vitro, this formulation potently inhibited inflammatory cytokine production on human myeloid cells. Our in-depth in vivo experiments provided evidence of the formulations potent plaque-stabilizing and anti-inflammatory actions. These effects were mediated by a shift in the monocyte/macrophage compartment toward homeostatic/repairing phenotypes. ConclusionsCollectively, our results demonstrate that HDL-associated PS potently suppresses inflammation and atheroprogression, and holds promise as a viable approach to improve immunomodulatory therapies.

immunology↗

bioRxiv2025

The Growth of Xiphophorus hellerii is Negatively Correlated with Colony Density

Xiphophorus fishes serve as important animal models in biomedical research. To investigate colony density influence on growth, we compared 6-, 9-, and 12-month-old fish raised in low- (1 fish/2L), mid- (1 fish/L), and high-density (2 fish/L) in re-circulating aquariums. As expected, the results indicate that fish reared in low-density aquariums exhibit the greatest growth, and fish reared in high-density aquariums result in the least growth.

zoology↗

bioRxiv2025

Intermittent Hypoxia Drives Early Metabolic Dysfunction in Brown Adipose Tissue

BackgroundObstructive sleep apnea (OSA) is associated with metabolic dysfunction, yet the early impact of intermittent hypoxia (IH)--a defining feature of OSA--on brown adipose tissue (BAT) remains unclear. MethodsWe investigated the direct and early effects of IH on BAT using both in vitro and in vivo approaches. Differentiated mouse brown adipocytes were exposed to IH for 48 hours and analyzed for {beta}3-adrenergic signaling, lipolysis, and thermogenic activation. Complementary in vivo studies assessed transcriptomic, morphological, and functional changes in BAT, white adipose tissue (WAT), and liver after 1 or 4 weeks of IH exposure in mice. ResultsIH blunted {beta}3-adrenergic signaling in cultured brown adipocytes, leading to reduced phosphorylation of key signaling proteins, impaired lipolytic response, and decreased expression of UCP1. In vivo, BAT exhibited early and sustained transcriptomic rewiring characterized by downregulation of pathways related to fatty acid metabolism, oxidative phosphorylation, and peroxisomal function. These molecular changes were accompanied by abnormal lipid droplet enlargement and a reduced lipolytic response to adrenergic stimulation. In contrast, WAT showed transient gene expression changes, and the liver displayed a delayed and robust transcriptomic response evident only after four weeks of IH exposure. Despite these metabolic alterations, thermogenic responses to cold challenge remained intact in IH-treated mice. ConclusionsBAT is uniquely and rapidly affected by intermittent hypoxia, undergoing functional, molecular, and morphological changes within one week of exposure. These alterations precede systemic inflammation and metabolic dysfunction, positioning BAT dysfunction as an early event in the pathogenesis of OSA-associated metabolic disease.

pathology↗

bioRxiv2025

Systematic cross-study assessment of RNA-Seq experimental workflows for plasma cell-free transcriptome profiling

Plasma cell-free RNA (cfRNA) is a promising source of non-invasive biomarkers, but its clinical translation is hindered by technical challenges and a lack of protocol standardization, which compromises reproducibility and comparability across studies. There is a need for a systematic evaluation of existing cfRNA-Seq workflows to understand the drivers of technical variability. Here, we address this gap by performing a comprehensive cross-study analysis of 2,166 cfRNA-Seq samples from 15 published studies and an in-house generated dataset, applying a uniform bioinformatics pipeline to enable a controlled comparison of experimental workflows. Our analysis reveals that the donor phenotype typically explains a negligible fraction of the transcriptomic variation, whose main determinants are technical - principally protocol choice, genomic DNA contamination levels and library diversity. Remarkably, this technical noise is so profound that variation within plasma cfRNA samples exceeds that found across a wide range of human tissues. Finally, we demonstrate that critical pre-analytical factors are often confounded with patient phenotypes, jeopardizing the validity of biomarker discovery efforts. Our work serves as a comprehensive benchmark of current cfRNA-Seq methodologies and provides evidence-based guidelines to improve experimental design. By highlighting the dominance of controllable technical factors, we offer a path towards more robust and reproducible cfRNA research.

bioinformatics↗

bioRxiv2025

MALDI-TIMS-MS2 Imaging and Annotation of Natural Products in Fungal-Bacterial Co-Culture

Mass spectrometry imaging (MSI) is a powerful tool for monitoring the spatial distributions of microbial metabolites directly from culture. MSI can identify secretion and retention patterns for microbial metabolites, allowing for the assessment of chemical communication within complex microbial communities. Microbial imaging via matrix-assisted laser desorption/ionization (MALDI) MSI remains challenging due to high sample complexity and heterogeneity associated with the required sample preparation, making annotation of molecules by MS1 alone challenging. The implementation of trapped ion mobility spectrometry (TIMS) has increased the dimensionality of MALDI-MSI experiments, allowing for the resolution of isomers and isobars, and can increase sensitivity of metabolite detection within complex samples. Parallel reaction monitoring - parallel accumulation serial fragmentation (prm-PASEF) leverages TIMS to enhance the targeted acquisition of MS2 data by increasing the number of precursors that can be fragmented in a single acquisition. Recently, imaging prm-PASEF (iprm-PASEF) has been developed to provide more accurate annotation from MALDI-TIMS-MSI datasets through the inclusion of MS2. Here, we showcase the use of MALDI iprm-PASEF to provide rapid and accurate annotation coproporphyrin III directly from a bacterial-fungal co-culture between Glutamicibacter arilaitensis (strain JB182) and Penicillium solitum (strain #12). Additionally, we present a workflow for untargeted iprm-PASEF precursor selection directly in SCiLS Lab, followed by direct export for iprm-PASEF acquisition. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/653367v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@5bef36org.highwire.dtl.DTLVardef@1b5f199org.highwire.dtl.DTLVardef@87ff8org.highwire.dtl.DTLVardef@98857_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2025

Imputation strategy for population DNA methylation sequencing data

BackgroundDNA methylation is a central epigenetic mechanism involved in regulating gene expression and responses to environmental factors. Although it can sometimes be passed down through generations, its heritability remains variable depending on the species and biological context. These characteristics make it a key marker for studying genotype-environment interactions. However, whole-genome sequencing for DNA methylation analysis remains costly when applied to large numbers of individuals, prompting researchers to focus on specific regions of interest. This targeted approach often results in data matrices with missing values for some individuals, which can hinder downstream analyses. ResultsOur study used 200 and 189 poplar and oak individuals from natural populations, respectively. We tested and compared seven methods for missing data imputation in the specific context of targeted DNA methylation sequencing data obtained in the three different DNA methylation contexts in plants (CpG, CHG, and CHH). The comparison of the different imputation result allows to evaluate their performance to determine the most suitable approach for this type of data. Among them, NIPALS, MissForest, and LOESS provided the highest accuracy. NIPALS delivered the best overall performance but with moderate computational cost, MissForest achieved similar accuracy with faster computation, and LOESS offered competitive results suitable for large datasets. ConclusionsOur results provide a reference for the selection of imputation strategies in targeted sequencing studies, improving the reliability of DNA methylation analyses and broadening the applicability of this type of data in epigenomic research. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/644107v2_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1c98f47org.highwire.dtl.DTLVardef@1dd9cfborg.highwire.dtl.DTLVardef@6d3a43org.highwire.dtl.DTLVardef@10c1d8b_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2024

Natural variation in chalcone isomerase defines a major locus controlling growth variation between Populus nigra populations

Poplar is a promising resource for wood production and the development of lignocellulosic biomass, but currently available varieties have not been optimized for these purposes. Therefore, it is critical to investigate the genetic variability and mechanisms underlying traits that affect biomass yield. Previous studies have shown that target traits in different poplar species are complex, with a small number of genetic factors having relatively low effects compared to medium to high heritability. In this study, a systems biology approach was implemented, combining genomic, transcriptomic, and phenotypic information from a large collection of individuals from natural populations of black poplar from Western Europe. Such an approach identified a QTL and a gene, coding for chalcone isomerase (CHI), as a candidate for controlling radial growth. Additionally, analysis of the structure and diversity of traits as well as CHI gene expression revealed a high allelic fixation index, linked to the geographical origin of the natural populations under study. These findings provide insights into how adaptive traits arise, are selected, and maintained in the populations. Overall, this study contributes to enhancing the use of poplar as a valuable resource for sustainable biomass production.

genomics↗

bioRxiv2024

Branched-chain amino acid catabolism promotes ovarian cancer cell proliferation via phosphorylation of mTOR

Ovarian cancer is the sixth leading cause of cancer-related mortality among individuals with ovaries, and high-grade serous ovarian cancer (HGSOC) is the most common and lethal subtype. Characterized by a distinct and aggressive metastatic pattern, HGSOC can originate in the fallopian tube with the transformation of fallopian tube epithelial (FTE) cells, which metastasize to the ovary and subsequently to the omentum and peritoneal cavity. The omentum is a privileged metastatic site, and the metabolic exchange underlying omental metastasis could provide enzyme or receptor targets to block spread. In this study, we adapted a mass spectrometry imaging (MSI) protocol to investigate spatial location of 3D cocultures of tumorigenic FTE cells when grown in proximity to murine omental explants as a model of early metastatic colonization. Our analysis revealed several altered metabolites in tumorigenic FTE/omentum cocultures, namely changes in branched-chain amino acids (BCAA), including valine. We quantified the heightened consumption of valine, other BCAAs, and other amino acid-derived metabolites in omental cocultures using LC-MS assays. Our analysis revealed that metabolite concentrations when monitored with MSI from cell culture media in living culture systems have notable considerations for how MSI data may produce signatures that induce ionization suppression. Supplementation with valine enhanced proliferation and mTOR signaling in tumorigenic FTE cells, suggesting the potential of BCAAs as a nutrient utilized by tumor cells during omental colonization and a possible target for metastasis. SIGNIFICANCEThis study uncovers altered amino acid metabolism, specifically increased BCAA catabolism, at the interface of ovarian cancer cells and omental tissue in a coculture model of HGSOC secondary metastasis. Enhanced BCAA catabolism may promote cancer cell proliferation through mTOR signaling, presenting potential therapeutic value. These findings deepen our understanding of HGSOC pathogenesis and the metastatic tumor microenvironment, offering insights for developing new treatment strategies.

cancer biology↗

bioRxiv2024

Red blood cell-tumour cell interactions promote tumour cell progression

One critical step in the metastatic cascade is the survival of circulating tumour cells (CTCs) within the bloodstream. While numerous interactions between CTCs and various hematopoietic cells have been described, the role of red blood cells (RBCs) in this process remains underexplored. This study investigates the interactions between tumour cells and RBCs from breast and lung cancer patients, revealing significant phenotypic and functional changes in the tumour cells, unlike when the contact is with RBCs from healthy donors. In vitro co-culture of cancer cell lines with RBCs from metastatic cancer patients resulted in increased tumour cell attachment accompanied by morphological changes. Additionally, RBCs-primed tumour cells showed increased adhesion and disruption of the endothelial barrier in vitro and increased invasiveness both in vitro and in vivo. Transcriptomic analysis showed that RBCs from metastatic breast cancer patients induce significant gene expression changes, notably upregulating PAK4, which enhances migration and epithelial-mesenchymal transition. PAK4 inhibition reduced these effects. Proteomic studies revealed substantial remodelling, including actin-related changes and the accumulation of VASP at cell edges, promoting directional migration. Clinically, higher RBC distribution width (RDW) in metastatic breast cancer patients is associated with increased CTC counts and worse outcome. This study highlights the previously unrecognized role of RBCs in promoting metastatic behaviours in cancer cells and suggests potential therapeutic targets, such as PAK4, to counteract these effects. Further exploration of RBCs-tumour cell interactions could provide new insights into metastatic mechanisms and improve cancer prognosis and treatment strategies. Key PointsO_LIThis study reveals the previously unknown role of RBCs in enhancing tumour cell invasiveness and metastatic potential. C_LIO_LITumour cells undergo significant phenotypic and functional changes after contact with RBCs from cancer patients. C_LI

cancer biology↗