Biology subjects

Tian, G.

Publications and source records attributed to Tian, G..

At least 19 recordsLinked to original sources

bioRxiv2026

Operator-valued free probability applied to recurrent neural networks with heterogeneity in local and global circuit structures

Random connectivity is a common assumption in models of recurrent neural networks, yet biological circuits combine heterogeneous synaptic connections with organization into distinct anatomical regions and functional groups. How does this global structure interact with cellular and local circuit heterogeneity to shape the dimensionality of population activity? In our work, we use operator-valued free probability to derive the covariance spectrum and effective dimension of recurrent networks with heterogeneous gains and block-structured random connectivity. This framework handles the noncommuting matrix operations through which cellular and circuit heterogeneity jointly determine population variability. We show that the linear relationship between effective dimension and firing rate uniformity persists despite global connectivity structure. At fixed total connectivity variance and with identical firing rate distributions across areas, concentrating variance within one area decreases dimension, whereas concentrating it in directed connections between areas increases dimension. Together, these results establish a mechanistic connection between circuit organization and population dimensionality, and demonstrate how operator-valued free probability unifies cellular, local, and global sources of heterogeneity in recurrent networks.

neuroscience↗

bioRxiv2026

Nucleoporin1 maintains male germ unit organization and transport in Arabidopsis pollen tubes, likely through shaping nuclear morphology

The male germ unit (MGU) in Arabidopsis pollen is comprised of one vegetative nucleus (VN) and two sperm nuclei (SN). It is evolutionarily specialized to deliver immotile sperm nuclei to an ovule for fertilization. Despite some progress in research on MGU, its organization and transport remain only partially understood. Here, we identified Nucleoporin1/136 as a new player in the structural organization and positioning of MGU in pollen tubes. We and others have previously reported the reduced fertility of nup1-1 plants; however, the mechanism remains unknown. In this work, we further examined the role of NUP1 in fertility using two mutant alleles, nup1-1 and nup1-2-/+. The reciprocal crosses between the nup1 mutants and the Col-0 wild type indicate that the nup1 mutant pollen is defective. To study the effect of a complete NUP1 knockout on pollen, we generated a transgenic line that produces pollen with and without NUP1 expression. This work led to the surprising discovery that the NUP1 protein is inherited from the pollen mother cell to the daughter cell during microgametophyte development. Subsequent in vitro experiments showed that NUP1 is required for pollen germination and pollen tube elongation. Further microscopic studies demonstrated that NUP1 is highly expressed in VN and essential for maintaining nuclear shape and size. We also demonstrated that NUP1 is required for proper MGU organization and transport, likely through maintaining VN morphology. Notably, our finding of nuclear morphology-mediated regulation of MGU may also explain the mechanistic details underlying the defective MGU movement in previously reported mutants such as kaku4, wit, and wip, which have abnormal nuclear morphology.

plant biology↗

bioRxiv2026

Microencapsulation of a novel Bacteroides thetaiotaomicron strain: a promising strategy to fortify intestinal barrier fortification in weaned pig model

Porcine Bacteroides thetaiotaomicron LYH5 demonstrated in vitro antimicrobial activity, suggesting probiotic potential. Due to poor gastric juice tolerance, LYH5 was encapsulated via extrusion using sodium alginate (SA) and gellan gum. Box-Behnken design optimization yielded optimal parameters: SA 1.5%, gellan gum 0.4%, CaCl2 0.9%, bacteria:glue ratio 1:4, achieving an encapsulation rate of 84.22{+/-}0.17%. Its effect on weaned piglet intestinal health was evaluated using 78 piglets (7.69{+/-}0.52 kg) randomly assigned to 4 groups for 40 days: CON (control), T (basal diet + LYH5 live bacteria, 1x10{superscript 1} CFU/mL), TJ (basal diet + LYH5 microcapsules, 1x10{superscript 1} CFU/mL, J (basal diet + empty capsules). The results of this experiment showed that compared with the control group, LYH5 microcapsule can improve the intestinal barrier function without affecting the growth performance of piglets, and provide ideas and references for the development of human next-generation probiotics (NGP). IMPORTANCEThis study addresses the key bottleneck of poor gastric acid tolerance of probiotics via microencapsulation and provides a practical reference for the development of human next-generation probiotics.

microbiology↗

bioRxiv2026

Noncanonical loops regulated by EMF1 and cohesin-associated factors shape the distinct 3D genome architecture in plants

In mammals, cohesin-mediated chromatin loop extrusion is blocked at boundaries, where CTCF, WAPL, and PDS5s co-bind and regulate cohesin, establishing an impermeable barrier with no exceptions. In contrast, our study revealed that in Arabidopsis, some noncanonical contacts have emerged between the boundary flanking regions, which suggest that cohesin is not absolutely blocked but enables sliding beyond boundaries. We identified these interactions as noncanonical loops and clarified their regulatory proteins. Firstly, the plant-specific boundary binding protein EMF1 is essential for noncanonical loops formation. Surprisingly, although both Arabidopsis WAPLs and PDS5s inhibit loop extension as mammals, PDS5s do not co-bind and cooperate with WAPLs at boundaries. Instead, PDS5s bind to boundary-flanking regions enriched with H3K4me1 through their Tudor domains, restricting further extension of noncanonical loops. Consequently, pds5a/b/c mutants lose noncanonical loops, resulting in emergence of larger canonical loops but anchored on boundaries and co-upregulation of anchored gene pairs. Collectively, our findings reveal that the plant-specific noncanonical loop, regulated by plant-specific EMF1 and PDS5 proteins, is the fundamental structure of the distinctive chromatin organization of plants, which provides novel mechanistic insights into eukaryotic chromatin architecture regulation.

plant biology↗

bioRxiv2025

Prolonged Loss of Oxidative Phosphorylation and Mitochondrial Mass Characterize CD66b+ Leukocytes from Patients with Sepsis

IntroductionSepsis leads to expansion of myeloid-derived suppressor cells (MDSC) and their subtypes. These normally transitory MDSCs suppress T cell activation and alter T cell cytokine production while simultaneously promulgating systemic low-grade inflammation. Immune metabolism can shape cell responses, regulate immune suppression, and enhance effector activity. Although MDSC metabolism has been extensively studied in cancer, the metabolic phenotype of this heterogeneous population in sepsis remains unclear. Our goal was to assess metabolic flux in blood MDSCs during and after sepsis and to stratify these patients clinical features and outcome with differences in metabolic flux that may guide treatment decisions. MethodsPeripheral blood mononuclear cells (PBMC) from healthy subjects and sepsis patients at 4 days, 2-3 weeks, and 6 months underwent CD66b+ or CD3+ enrichment, followed by assessment of metabolic flux, flow cytometry, mRNA sequencing, and chromatin accessibility. ResultsMitochondrial basal oxygen consumption rates (OCR) and maximal oxygen consumption rates (SRC, spare respiratory capacity) were decreased in MDSC from septic patients at 4 days after infection and persisted for up to 6 months after sepsis onset. Sepsis was not associated with differences in glycolysis. In contrast, oxidative metabolism in CD3+ T cells was similar between sepsis patients and healthy subjects. Reduced MDSC oxidative metabolism was linked to adverse clinical outcomes. The decline in oxygen consumption from MDSCs in septic patients was also associated with significant reductions in MDSC mitochondrial content. Transcriptomic analysis of CD66b+ cells isolated from PBMC of healthy participants and patients with sepsis at 4 days, 2-3 weeks, and 6 months revealed 19 differentially expressed genes and three long non-coding RNAs as potentially responsible for this decline in mitochondrial mass. Specifically, NR4A3, NR4A2, and TAMLIN/NR4A1 expression, all critical for mitochondrial biogenesis, were persistently decreased with reduced chromatin accessibility indicative of gene silencing. DiscussionAfter sepsis, blood CD66b+ cells present with reduced mitochondrial mass and oxidative metabolism that continue at least 6 months after sepsis. These changes in mitochondrial function result from a reduced content of these organelles. We have also identified gene silencing, reduced gene expression of key transcription factors that regulate mitochondrial biogenesis, as well as increased long non-coding RNA as potential drivers of this unique metabolic phenotype. These results highlight the potential benefit of targeting metabolism in sepsis to promote immune homeostasis and recovery.

immunology↗

bioRxiv2025

Structural and biochemical studies of human PP2A(B55) holoenzyme and ENSA protein complex

The serine/threonine protein phosphatase 2A (B55) holoenzyme (PP2A(B55)), a key cell cycle regulator, is tightly regulated by ENSA, whose phosphorylation at Ser67 inhibits PP2A(B55). The structural basis for how pENSA orchestrates this inhibition to govern mitotic progression remains unclear. In this study, we disapproved the previous hypothesis of direct ENSA-PP2A A subunit interaction, and showed that the ENSA-PP2A(B55) interaction requires the PP2A holoenzyme. We then determined cryo-EM structure of the PP2A(B55)-ENSAS67D complex at 3.03 [A] resolution, which reveals four distinct regions of ENSA, each engaging specific sites on the B55 or C subunits. The structure reveals an extended, inhibited conformation of the PP2A(B55) holoenzyme, which contrasts sharply with the contracted, active state of apo PP2A(B55). pENSA binding induces the C subunit to shift away from the B55 subunit, with the pS67-containing motif inserting into the catalytic site of C subunit and locking the PP2A(B55) holoenzyme in an inactive state. Our work also revealed novel ligand-binding surfaces on B55, and expanded definition of the short linear motif (SliM). Overall, our work provided novel insights into PP2A regulation during cell cycle, and offers new avenues for the discovery of specific PP2A(B55) inhibitors and modulators.

biophysics↗

bioRxiv2025

An ancient transcription factor functions as the master regulator of primary cilia formation

How ancient transcription factors are repurposed during evolution to drive the functional diversification of conserved organelles remains a fundamental question in biology. Although highly conserved in basic morphology, eukaryotic cilia vary extensively in their sizes and functions. Previously, we showed that an evolutionarily ancient transcription factor, X chromosome-associated protein 5 (Xap5), controls motile ciliogenic transcriptional programs during mouse spermatogenesis (Wang et al., 2025). Here we show that Xap5 functions as the master regulator of primary ciliogenesis. Xap5 associates with the nuclear protein Non-POU domain-containing octamer-binding protein (Nono) to form a regulatory module that directly binds and activates the transcription factors Sox5 and Sox9. Genetic ablation of Xap5 or Nono impairs primary ciliogenesis, and loss of Sox5 disrupts the downstream ciliogenic program, consistent with the established role of Sox9. Collectively, our results provide new insight into how complex ciliary transcription factor networks determine ciliary diversity during evolution, and suggest that defects in this regulatory axis may contribute to the etiology of human ciliopathies.

cell biology↗

bioRxiv2025

Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks

Psilocybin holds promise as a treatment for mental illnesses. One dose of psilocybin induces structural remodeling of dendritic spines in the medial frontal cortex in mice. The dendritic spines would be innervated by presynaptic neurons, but the sources of these inputs have not been identified. Here, using monosynaptic rabies tracing, we map the brain-wide distribution of inputs to frontal cortical pyramidal neurons. We discover that psilocybins effect on connectivity is network-specific: strengthening the routing of inputs from perceptual and medial regions (homolog of default mode network) to subcortical targets, while weakening inputs that are part of cortico-cortical recurrent loops. The pattern of synaptic reorganization depends on the drug-evoked spiking activity, because silencing a presynaptic region during psilocybin administration disrupts the rewiring. Collectively, the results reveal the impact of psilocybin on the connectivity of large-scale cortical networks and demonstrate neural activity modulation as an approach to sculpt the psychedelic-evoked neural plasticity.

neuroscience↗

bioRxiv2025

Toward Crosstalk-free All-optical Interrogation of Neural Circuits

All-optical interrogation, based on high-resolution two-photon stimulation and imaging, has emerged as a potentially transformative approach in neuroscience, allowing for the simultaneous precise manipulation and monitoring of neuronal activity across various model organisms. However, the unintended excitation of light-gated ion channels such as channelrhodopsin (ChR) during two-photon calcium imaging with genetically encoded calcium indicators (GECIs) introduces artifactual neuronal perturbation and contaminates neural activity measurements. In this study, we propose an active pixel power control (APPC) approach, which dynamically adjusts the imaging laser power at each scanning pixel, to address the challenge. We aim to achieve simultaneous two-photon optogenetic manipulation and calcium imaging with a single femtosecond laser, while minimizing the crosstalk between manipulation and imaging. To study this technologys capabilities, we applied it to the larval zebrafish brain in vivo. Our results demonstrate that the APPC approach preserves GECI signal quality while suppressing optogenetic artifacts significantly. This enhances the accuracy of neural circuit dissection and advances the precision of all-optical interrogation, offering a robust framework for probing neural circuit dynamics and causality in vivo with high fidelity, potentially across various model organisms. Importantly, this technology can be seamlessly integrated with commonly used two-photon microscope systems in laboratories worldwide.

neuroscience↗

bioRxiv2025

Treatment Resistant Persister Cells Exploit Macrophage Lipid Metabolism to Sustain Glioblastoma Growth

Glioblastoma (GBM) displays pronounced intratumoral heterogeneity, posing significant challenges to understanding its biology and developing effective treatments. Using spatial multi-omics, in vivo functional assays, and systems-level analysis, we delineate the diverse metabolic and immune architecture of GBM. We identify a lipid-dependent lineage of treatment-resistant persister cells (TRPCs) that engage tumor-associated macrophages (TAMs) in a spatially organized, metabolically specialized crosstalk. TRPCs co-opt CCR2, CSF1R, CD163+ TAMs for lipid scavenging and acquisition, promoting a pro-tumorigenic and immunosuppressive microenvironment. This cooperative axis is critically dependent on lipid chaperones like FABPs, whose targeting disrupts TAM recruitment, remodels immune composition, and suppresses tumor growth. Retrospective clinical analyses reveal that elevated TRPC-associated transcriptome may serve as stratification criteria to identify patients benefiting from lipid-lowering therapies like statins. Our findings uncover a targetable immunometabolic circuit between TRPCs and TAMs and support the development of precision therapies that disrupt lipid-fueled tumor-immune cooperation in GBM. In briefTreatment-resistant persister cells (TRPCs) in glioblastoma spatially engage TAMs to facilitate lipid transfer, thereby sustaining tumor growth and promoting immune evasion. Targeting this TRPC-TAM metabolic axis reprograms the immunosuppressive microenvironment and improves therapeutic outcomes, revealing a clinically actionable metabolic vulnerability with potential for precision immune-metabolic interventions in GBM. HighlightsO_LIGBM exhibits spatially resolved heterogeneity revealing correlative metabolic and immune micro-niches C_LIO_LITRPC lineage promotes a pro-tumorigenic and immunosuppressive microenvironment by recruiting lipid-specialized TAMs C_LIO_LITRPC lineage hijacks TAMs for metabolic support via stimulating lipid transfer and acquisition C_LIO_LIDisruption of the TRPC-TAM lipid axis, including through FABP3 targeting, reprograms the immune landscape, limits TAM recruitment, and impairs tumor progression C_LIO_LITRPC lineage and associated micro-niche transcriptomic profiles can serve as criteria for patient stratification and identification of responders to lipid-lowering therapies, such as statins C_LI

cancer biology↗

bioRxiv2025

Neuropeptide signalling and perineurial barrier generate a persistent stress-induced internal state in Drosophila

Although fear conditioning has elucidated cue-evoked acute fear responses, the mechanisms by which stress experiences induce generalized internal states linked to anxiety are poorly understood. Here, we report that robust stress induces a persistent behavioral change characterized by avoidance of a confined space, claustrophobia-like behavior in Drosophila. Unlike aversive memory formation, the development of claustrophobia-like behavior does not require dopamine receptors. Our neuronal screening determined that neuropeptide signalling via Allatostatin-A inactivates the downstream neurons via its receptor AstA-R1, causally inducing claustrophobia-like behavior. Moreover, gene expression profiling of individual fly heads revealed that immune response activation in perineurial barrier is involved in claustrophobia-like behavior. Our data demonstrate that stress-induced persistent behavioral change would not be related to a canonical mechanism of aversive memory formation, rather involves neuropeptidergic signalling and perineurial barrier, providing the mechanism determining internal states which persistently change behavioral modes.

neuroscience↗

bioRxiv2025

IL-18 metabolically reprograms CAR-expressing natural killer T cells and enhances their antitumor activity against neuroblastoma

Invariant natural killer T cells (NKTs) have intrinsic anti-tumor properties that make them promising candidates for chimeric antigen receptor (CAR)-based immunotherapies. Transgenic cytokine expression has been shown to enhance the potency of cellular immunotherapies, and we hypothesized that co-expressing IL-18 alone or with IL-15 would boost CAR-NKT therapeutic potential. To test this hypothesis, we generated retroviral constructs expressing IL-15 and/or IL-18 with the inducible caspase 9 (iC9) safety switch and co-transduced them with a GD2-specific CAR into human NKTs. Co-expression of IL-18 or IL-15/IL-18 increased GD2.CAR-NKT in vitro cytotoxicity, proliferation, and cytokine secretion compared to IL-15 alone. In a metastatic neuroblastoma model, GD2.CAR-NKTs expressing constructs with IL-18 controlled tumor growth better than cells expressing IL-15 only, but mice in the IL-15/IL-18 group developed severe toxicities not observed in the IL-18-only group. Mechanistically, we found that IL-18 drives a distinct transcriptional profile from IL-15 in CAR-NKTs marked by lower expression of exhaustion gene signatures and enrichment of metabolism-related processes. Finally, targeted metabolomics revealed that IL-18 induces broad metabolic reprogramming in CAR-NKTs including enhancement of oxidative phosphorylation, glycolysis, glutaminolysis and purine metabolism. These results support the use of IL-18 in developing the next generation of cytokine-armed CAR-NKT cancer immunotherapy.

immunology↗

bioRxiv2024

Neuronal Detection Triggers Systemic Digestive Shutdown in Response to Adverse Food Sources

The ability to sense and adapt to adverse food conditions is essential for survival across species, but the detailed mechanisms of neuron-digestive crosstalk in food sensing and adaptation remain poorly understood. This study identifies a novel mechanism by which animals detect unfavorable food sources through neurons and initiate a systemic response to shut down digestion, thus safeguarding against potential harm. Specifically, we demonstrate that NSY-1, expressed in AWC neurons, detects Staphylococcus saprophyticus (SS) as an unfavorable food source, prompting the animal to avoid and halt digestion of SS. Upon detection, the animals activate the AWCOFF neural circuit, leading to a systemic digestive shutdown, which is mediated by NSY-1-dependent STR-130. Additionally, NSY-1 mutation triggers the production of insulin peptides, including INS-23, which interact with the DAF-2 receptor to modulate SS digestion and affects the expression of intestinal BCF-1. These findings uncover a crucial survival strategy through neuron-digestive crosstalk, where the NSY-1 pathway in AWC neurons orchestrates food evaluation and initiates digestive shutdown to adapt effectively to harmful food sources.

physiology↗

bioRxiv2024

Bacterial sensing via Neuronal Receptor Initiates Gut Mitochondrial Surveillance for Host Adaptation

Animals exist within a microbial world and are constantly challenged by pathogen infections. Microbe-mediated protection for against infection is the survival strategy for host. However, elucidating specific microbial molecules and understanding how they interact with the hosts intracellular surveillance system for protection is difficult but highly desirable. Here, by establishing "pathogen-like-bacteria" screening system, we identified E. coli mutants, including {Delta}ymcB, that act as "pathogen-like-bacteria" to defend animals against Pseudomonas aeruginosa PA14 infection by activating UPRmt. Additionally, through genetic screening, we identified neuronal transmembrane protein, MDSS-1, that is crucial for sensing {Delta}ymcB and activating intestinal UPRmt. Moreover, we demonstrated that MDSS-1 functions as a receptor in ASE neurons, responsible for detecting {Delta}ymcB. It then communicates microbial signals through neuropeptides, GPCR, Wnt signaling and endopeptidase inhibitors to trigger intestinal UPRmt, that defends the host animals against infections. Furthermore, Constitutionally activation of MDSS-1 in ASE neurons is sufficient to trigger intestinal UPRmt in animals, resulting in protection against infection. Our study uncovers an intriguing mechanism involving intracellular mitochondrial surveillance, where neuron-intestine crosstalk originates from ASE neurons to detect bacteria and combat pathogens. This study identifies a bacteria-sensing mechanism in neurons that regulates intestinal mitochondrial surveillance pathway for host adaptation. HighlightsO_LIEstablishment of "pathogen-like-bacteria" screening system in C. elegans C_LIO_LI{Delta}ymcB promotes animal defend against infections via triggering UPRmt C_LIO_LINeuronal MDSS-1, a single transmembrane protein, detects "pathogen-like-bacteria" C_LIO_LIActivated-MDSS-1 induces distant UPRmt via inter-tissue communication factors C_LI

physiology↗

bioRxiv2024

Integration of binocular vision and motor state to promote prey pursuit

Most animals with two eyes combine the inputs to achieve binocular vision, which can serve numerous functions, and is particularly useful in hunting prey. However, the mechanisms by which visual information from the two eyes are combined remain largely unknown. Here, we designed a device to reversibly occlude the eyes of a head-fixed zebrafish larva, and used large-scale volumetric two-photon imaging to identify binocular neurons that respond to prey stimuli. We found these binocular prey-responsive neurons (bino-PRNs) were primarily located in three areas, the pretectum, thalamus, and nucleus isthmi. We then characterized the bino-PRNs functional properties, and found that their left and right eye receptive fields are offset to varying degrees, which would correspond to objects at naturalistic hunting distances for a larva with converged eyes. We also found that bino-PRNs have a significantly greater response in hunting trials, which could be the result of an eye convergence-related corollary discharge. We then optogenetically induced prey capture eye and tail movements, and found that this hunting command activates prey responsive neurons in the pretectum, thalamus, and nucleus isthmi. These findings indicate that bino-PRNs receive visual and motor input that would allow them to encode prey position in three dimensions.

neuroscience↗

bioRxiv2024

Molecular and circuit determinants in the globus pallidus mediating control of cocaine-induced behavioral plasticity

The globus pallidus externus (GPe) is a central component of the basal ganglia circuit, receiving strong input from the indirect pathway and regulating a variety of functions, including locomotor output and habit formation. We recently showed that it also acts as a gatekeeper of cocaine-induced behavioral plasticity, as inhibition of parvalbumin-positive cells in the GPe (GPePV) prevents the development of cocaine-induced reward and sensitization. However, the molecular and circuit mechanisms underlying this function are unknown. Here we show that GPePV cells control cocaine reward and sensitization by inhibiting GABAergic neurons in the substantia nigra pars reticulata (SNrGABA), and ultimately, selectively modulating the activity of ventral tegmental area dopamine (VTADA) cells projecting to the lateral shell of the nucleus accumbens (NAcLat). A major input to GPePV cells is the indirect pathway of the dorsomedial striatum (DMSD2), which receives DAergic innervation from collaterals of VTADA[->]NAcLat cells, making this a closed-loop circuit. Cocaine likely facilitates reward and sensitization not directly through actions in the GPe, but rather in the upstream DMS, where the cocaine-induced elevation of DA triggers a depression in DMSD2 cell activity. This cocaine-induced elevation in DA levels can be blocked by inhibition of GPePV cells, closing the loop. Interestingly, the level of GPePV cell activity prior to cocaine administration is correlated with the extent of reward and sensitization that animals experience in response to future administration of cocaine, indicating that GPePV cell activity is a key predictor of future behavioral responses to cocaine. Single nucleus RNA-sequencing of GPe cells indicated that genes encoding voltage-gated potassium channels KCNQ3 and KCNQ5 that control intrinsic cellular excitability are downregulated in GPePV cells following a single cocaine exposure, contributing to the elevation in GPePV cell excitability. Acutely activating channels containing KCNQ3 and/or KCNQ5 using the small molecule carnosic acid, a key psychoactive component of Salvia rosmarinus (rosemary) extract, reduced GPePV cell excitability and also impaired cocaine reward, sensitization, and volitional cocaine intake, indicating its potential as a therapeutic to counteract psychostimulant use disorder. Our findings illuminate the molecular and circuit mechanisms by which the GPe orchestrates brain-wide changes in response to cocaine that are required for reward, sensitization, and self-administration behaviors.

neuroscience↗

bioRxiv2024

The enzyme glutamate-cysteine ligase (GCL) is a target for ferroptosis induction in cancer

Despite glutathiones long-recognized role as a major cellular antioxidant and its central role in ferroptosis defense, inhibition of glutathione biosynthetic enzymes has received little attention as a target for the therapeutic induction of ferroptosis. Here, we report that small-molecule inhibition of glutamate-cysteine ligase (GCL), the rate-limiting enzyme of glutathione biosynthesis, selectively and potently kills cancer cells by ferroptosis. We further describe novel GCL inhibitors including KOJ-1 and KOJ-2, compounds with excellent cellular potency and pharmacological properties, representing valuable tools to study the biology of ferroptosis and glutathione.

cancer biology↗

bioRxiv2024

KR158 spheres harboring slow-cycling cells recapitulate GBM features in an immunocompetent system

Glioblastoma (GBM) poses a significant challenge in clinical oncology due to its aggressive nature, heterogeneity, and resistance to therapies. Cancer stem cells (CSCs) play a critical role in GBM, particularly in treatment-resistance and tumor relapse, emphasizing the need to comprehend the mechanisms regulating these cells. Also, their multifaceted contributions to the tumor-microenvironment (TME) underline their significance, driven by their unique properties. This study aimed to characterize glioblastoma stem cells (GSCs), specifically slow-cycling cells (SCCs), in an immunocompetent murine GBM model to explore their similarities with their human counterparts. Using the KR158 mouse model, we confirmed that SCCs isolated from this model exhibited key traits and functional properties akin to human SCCs. KR158 murine SCCs, expanded in the gliomasphere assay, demonstrated sphere forming ability, self-renewing capacity, positive tumorigenicity, enhanced stemness and resistance to chemotherapy. Together, our findings validate the KR158 murine model as a framework to investigate GSCs and SCCs in GBM-pathology, and explore specifically the SCC-immune system communications, understand their role in disease progression, and evaluate the effect of therapeutic strategies targeting these specific connections.

cancer biology↗