Biology subjects

Lathia, J.

Publications and source records attributed to Lathia, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Metabolic engineering of Salmonella enterica for coupled kynurenine sensing and depletion enhances antitumor efficacy

Immunosuppressive tumor metabolic microenvironment remains a major barrier to effective cancer therapy. Tumor-targeting Salmonella enterica strains were engineered to deplete the intratumoral immunosuppressive kynurenine, triggering metabolic rewiring and fostering an active antitumor immune microenvironment. Equipping S. enterica VNP20009 with bacterial kynureninase enzyme (KynU) and a kynurenine transporter enabled efficient intratumoral kynurenine degradation. We then developed a next-generation strain, AD51, combining quorum-sensing controlled KynU expression with kynurenine-dependent growth and tumor targeting. AD51 induced robust immune activation and exhibited better anti-tumor efficacy. The addition of intratumoral exogenous IFN{gamma} to AD51 synergistically enhanced immune activation and antitumor efficacy in murine ovarian cancer and melanoma models, reducing tumor burden by 75% and 84%, respectively, compared with untreated controls (p<0.0001 for both). Our data establishes a framework for engineering bacteria to target and degrade tumor immunosuppressive metabolites while coupling bacterial growth to metabolite availability, paving the way for more precise and programmable microbial therapies.

cancer biology↗

bioRxiv2026

Hemodynamic Signals Reshape Biological Inference in Widefield Calcium Imaging

Widefield calcium imaging is widely used to study cortex-wide neural dynamics, yet fluorescence signals are strongly influenced by hemodynamic fluctuations arising from blood volume and oxygenation changes. Although hemodynamic correction is frequently applied, it remains unclear whether vascular contributions represent a modest preprocessing concern or systematically bias biological interpretations of cortical activity. Here, we used dual-wavelength imaging to determine how hemodynamic correction reshapes inference of cortical dynamics across mouse lines expressing GCaMP6s, GCaMP6f, and jGCaMP8m, across multiple analytical domains, and under healthy and glioblastoma conditions. We systematically compared uncorrected and corrected signals using analyses spanning functional parcellation, connectivity, spectral structure, brain-behavior coupling, and low-dimensional network-state dynamics. Hemodynamic correction consistently reduced global functional connectivity, increased network modularity, redistributed spectral power away from slow-frequency dominance, and reorganized multivariate representations of cortical state space. These findings demonstrate that vascular signals do not behave as unstructured measurement noise but instead introduce organized variance that propagates across analytical pipelines and influences inference of cortical dynamics. The consequences of this bias were particularly relevant in glioblastoma, where tumor-associated vascular remodeling amplifies the mismatch between fluorescence signals and underlying neuronal activity. In this disease setting, correction revealed hemispheric asymmetries, reduced network-state entropy, and constrained trajectories within cortical state space that were obscured in uncorrected recordings, demonstrating that vascular remodeling can fundamentally alter interpretation of tumor-associated brain dynamics. More broadly, vascular signals systematically biased estimates of functional organization, network architecture, brain-behavior relationships, and disease-associated phenotypes. Together, these findings establish hemodynamic correction as a critical determinant of biological interpretation in mesoscale calcium imaging rather than a simple preprocessing refinement.

neuroscience↗

bioRxiv2026

NeuroPupil: A generalization-first framework for scalable and biologically informative cross-species pupillometry

Quantitative pupillometry provides a noninvasive window into brain state and neurological function, but its broader use across experimental and clinical settings is limited by challenges in achieving accurate, scalable, and generalizable measurements. Here, we present NeuroPupil, a deep learning framework for high-throughput, cross-species pupillometry that emphasizes robust generalization across subjects, behavioral contexts, and imaging conditions. Through systematic benchmarking of training strategies and network architectures, we identify pooled multi-subject training combined with an optimized U-Net architecture as a key determinant of reliable and transferable pupil tracking performance. Across diverse mouse and human datasets, NeuroPupil achieves improved accuracy and substantial gains in computational efficiency compared to existing approaches, enabling practical analysis of large-scale datasets. We further demonstrate that improved pupil tracking fidelity enhances downstream biological inference: NeuroPupil-derived pupil features significantly improve prediction of distributed cortical activity in behaving mice and preserve diagnostically relevant temporal structure in human clinical recordings. These findings highlight the importance of precise and scalable measurement for linking pupil dynamics to brain activity and clinical phenotypes. By integrating benchmarking, scalability, and accessible software tools, NeuroPupil provides a reproducible framework for large-scale pupillometry and facilitates its application in systems and translational neuroscience.

neuroscience↗

bioRxiv2025

Platelets drive immune suppression and glioblastoma growth in a sex-dependent manner via PAR4 signaling

Sex differences in cancer outcome, including that of glioblastoma (GBM), are shaped by biological, hormonal, and immunological factors and impact disease progression, treatment responses, survival, and tumor microenvironment (TME) interactions. Platelets regulate the immune responses and tumor progression in many cancers, but it is not clear how they contribute to these sex-based differences by affecting the dynamics of the TME. Here, we show that GBM patients exhibit heightened platelet reactivity driven by PAR4 signaling. In murine GBM models, both pharmacological inhibition of PAR4 using BMS986120 and genetic deletion of PAR4 significantly prolong survival in females but not males. This survival advantage is estrogen dependent: it is preserved in chromosomal male-hormonal female mice within the four-core genotype model and is rescued in ovariectomized mice treated with estrogen. The survival benefit is TME specific and is mediated by platelet-driven enhancement of CD8 T cell infiltration into the tumor. Inhibition of platelet PAR4 signaling increases calcium signaling through an estrogen-dependent interaction between PAR4 and estrogen receptor {beta} (ER{beta})--a receptor interaction not previously described. PAR4-activated platelets within the TME suppress CD8 T cell function, and depletion of CD8 T cells abolishes both the tumor-induced platelet reactivity and the survival benefit conferred by PAR4 inhibition. These findings establish platelet-mediated PAR4 signaling as a critical driver of tumor progression and identify sex-specific immune responses as key to therapeutic efficacy.

cancer biology↗

bioRxiv2024

γ-aminobutyric acid receptor B signaling drives glioblastoma in females in an immune-dependent manner

Sex differences in immune responses impact cancer outcomes and treatment response, including in glioblastoma (GBM). However, host factors underlying sex specific immune-cancer interactions are poorly understood. Here, we identify the neurotransmitter {gamma}-aminobutyric acid (GABA) as a driver of GBM-promoting immune response in females. We demonstrated that GABA receptor B (GABBR) signaling enhances L-Arginine metabolism and nitric oxide synthase 2 (NOS2) expression in female granulocytic myeloid-derived suppressor cells (gMDSCs). GABBR agonist and GABA analog promoted GBM growth in females in an immune-dependent manner, while GABBR inhibition reduces gMDSC NOS2 production and extends survival only in females. Furthermore, female GBM patients have enriched GABA transcriptional signatures compared to males, and the use of GABA analogs in GBM patients is associated with worse short-term outcomes only in females. Collectively, these results highlight that GABA modulates anti-tumor immune response in a sex-specific manner, supporting future assessment of GABA pathway inhibitors as part of immunotherapy approaches.

cancer biology↗

bioRxiv2024

miR-644a is a tumor cell-intrinsic mediator of sex bias in glioblastoma

BackgroundBiological sex is an important risk factor for glioblastoma (GBM), with males having a higher incidence and poorer prognosis. The mechanisms for this sex bias are thought to be both tumor intrinsic and tumor extrinsic. MicroRNAs (miRNAs), key post-transcriptional regulators of gene expression, have been previously linked to sex differences in various cell types and diseases, but their role in the sex bias of GBM remains unknown. MethodsWe leveraged previously published paired miRNA and mRNA sequencing of 39 GBM patients (22 male, 17 female) to identify sex-biased miRNAs. We further interrogated a separate single-cell RNA sequencing dataset of 110 GBM patients to examine whether differences in miRNA target gene expression were tumor cell intrinsic or tumor cell extrinsic. Results were validated in a panel of patient-derived cell models. ResultsWe identified 10 sex-biased miRNAs (adjusted < 0.1), of which 3 were more highly expressed in males and 7 more highly expressed in females. Of these, miR-644a was higher in females, and increased expression of miR-644a target genes was significantly associated with decreased overall survival (HR 1.3, p = 0.02). Furthermore, analysis of an independent single-cell RNA sequencing dataset confirmed sex-specific expression of miR-644a target genes in tumor cells (p < 10-15). Among patient derived models, miR-644a was expressed a median of 4.8-fold higher in females compared to males. ConclusionsOur findings implicate miR-644a as a candidate tumor cell-intrinsic regulator of sex-biased gene expression in GBM. Key PointsO_LImiR-644a is more highly expressed in female GBM patients. C_LIO_LILower miR-644a target gene expression is associated with improved overall survival. C_LIO_LImiR-644a target genes are higher in male GBM cells but not in other cell types. C_LI Importance of the StudyMicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression at the post-transcriptional level and were previously linked to glioblastoma (GBM) growth and therapeutic resistance. miRNAs play a role in the sex bias of various cell types and diseases, but how miRNAs contribute to sex differences in GBM is not well elucidated. We show that 10 miRNAs are differentially expressed between males and females and identify miR-644a as more highly expressed in female GBM patients. Using single-cell RNA-seq data, we demonstrate that sex differences in miR-644a target gene expression are tumor cell-intrinsic. Likewise, decreased miR-644a target gene expression is associated with improved overall patient survival. Our findings reveal miR-644a as a novel sex-biased miRNA in GBM, and a possible target for sex-specific precision therapies with limited collateral damage.

cancer biology↗

bioRxiv2023

Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition

The glioblastoma microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly impact the immune system, but the mechanisms driving these interactions are not completely clear. Here we demonstrate that the polyamine metabolite spermidine is elevated in the glioblastoma tumor microenvironment. Exogenous administration of spermidine drives tumor aggressiveness in an immune-dependent manner in pre-clinical mouse models via reduction of CD8+ T cell frequency and phenotype. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in spermidine synthesis, did not impact cancer cell growth in vitro but did result in extended survival. Furthermore, glioblastoma patients with a more favorable outcome had a significant reduction in spermidine compared to patients with a poor prognosis. Our results demonstrate that spermidine functions as a cancer cell-derived metabolite that drives tumor progression by reducing CD8+T cell number and function.

cancer biology↗

bioRxiv2022

Iron Inhibits Glioblastoma Cell Migration and Polarization

Glioblastoma is one of the deadliest malignancies facing modern oncology today. The ability of glioblastoma cells to diffusely spread into neighboring healthy brain makes complete surgical resection nearly impossible and contributes to the recurrent disease faced by most patients. Although research into the impact of iron on glioblastoma has addressed proliferation, there has been little investigation into how cellular iron impacts the ability of glioblastoma cells to migrate - a key question especially in the context of the diffuse spread observed in these tumors. Herein, we show that increasing cellular iron content results in decreased migratory capacity of human glioblastoma cells. The decrease in migratory capacity was accompanied by a decrease in cellular polarization in the direction of movement. Expression of CDC42, a Rho GTPase that is essential for both cellular migration and establishment of polarity in the direction of cell movement, was reduced upon iron treatment. Bioinformatic analysis of CDC42 mRNA revealed a potential iron-responsive element that may contribute to the regulation of CDC42 by iron. We then analyzed a single-cell RNA-seq dataset of human glioblastoma samples and found that cells at the tumor periphery had a gene signature that is consistent with having lower levels of cellular iron. Altogether, our results suggest that cellular iron content is impacting glioblastoma cell migratory capacity and that cells with higher iron levels exhibit reduced motility.

cancer biology↗

bioRxiv2022

Tumor cell-intrinsic HFE drives glioblastoma growth

BackgroundGlioblastoma (GBM) tumor cells modulate expression of iron-associated genes to enhance iron uptake from the surrounding microenvironment, driving proliferation and tumor growth. The homeostatic iron regulator (HFE) gene, encoding the iron sensing HFE protein, is upregulated in GBM and correlates with poor survival outcomes. However, the molecular mechanisms underlying these observations remain unclear. Identification of pathways for targeting iron dependence in GBM tumors is therefore a critical area of investigation. MethodsWe interrogated the impact of cell-intrinsic Hfe expression on proliferation and tumor growth through genetic loss and gain of function approaches in syngeneic mouse glioma models. We determined the expression of iron-associated genes and their relationship with survival in GBM using public datasets and identified differentially expressed pathways in Hfe knockdown cells through Nanostring transcriptional profiling. ResultsLoss of Hfe induced apoptotic cell death in vitro and inhibited tumor growth in vivo while overexpression of Hfe accelerated both proliferation and tumor growth. Analysis of iron gene signatures in Hfe knockdown cells revealed alterations in the expression of several iron-associated genes, suggesting global disruption of intracellular iron homeostasis. Analyzing differentially expressed pathways further identified oxidative stress as the top pathway upregulated with Hfe loss. Enhanced 55Fe uptake and generation of reactive oxygen species (ROS) were found with Hfe knockdown, implicating toxic iron overload resulting in apoptotic cell death. ConclusionsCollectively, these findings identify a novel role for HFE in regulating iron homeostasis in GBM tumors and provide a potential avenue for future therapeutic development. Key PointsO_LIHFE is an iron sensor that is upregulated in GBM and negatively impacts survival. C_LIO_LIHFE overexpression drives proliferation and tumor growth in vivo. C_LIO_LILoss of HFE increases production of reactive oxygen species and induces apoptosis, extending survival in vivo. C_LI Importance of StudyDysregulation of iron metabolism is an important feature of GBM contributing to tumor growth and negatively impacting survival. The identification of key iron regulators controlling this process is therefore important for therapeutic targeting. We identify HFE as an important regulator of iron homeostasis in GBM and suggest a role for sexual dimorphism in HFE-mediated tumor iron regulation that ultimately results in differential survival outcomes. Our findings demonstrate that HFE drives tumor cell proliferation and survival in GBM and may be a viable target for modulating tumor iron flux and inducing apoptosis in tumor cells.

cancer biology↗

bioRxiv2022

The MIF SNP rs755622 is a germline determinant of tumor immune activation in Glioblastoma

While immunotherapies have shown durable responses for multiple tumors, their efficacy remains limited in some advanced cancers, including glioblastoma. This may be due to differences in the immune landscape, as the glioblastoma microenvironment strongly favors immunosuppressive myeloid cells, which are linked to an elevation in immune-suppressive cytokines, including macrophage migration inhibitory factor (MIF). We now find that a single-nucleotide polymorphism (SNP) rs755622 in the MIF promoter associates with increased leukocyte infiltration in glioblastoma. Furthermore, we identified lactotransferrin expression as being associated with the rs755622 SNP, which could also be used as a biomarker for immune infiltrated tumors. These findings provide the first example in glioblastoma of a germline SNP that underlies differences in the immune microenvironment and identifies high lactotransferrin as a potential factor promoting immune activation.

cancer biology↗

bioRxiv2022

VRK1 is a Paralog Synthetic Lethal Target in VRK2-methylated Glioblastoma

Synthetic lethality -- a genetic interaction that results in cell death when two genetic deficiencies co-occur but not when either deficiency occurs alone -- can be co-opted for cancer therapeutics. A pair of paralog genes is among the most straightforward synthetic lethal interaction by virtue of their redundant functions. Here we demonstrate a paralog-based synthetic lethality by targeting Vaccinia-Related Kinase 1 (VRK1) in Vaccinia-Related Kinase 2 (VRK2)-methylated glioblastoma (GBM). VRK2 is silenced by promoter methylation in approximately two-thirds of GBM, an aggressive cancer with few available targeted therapies. Genetic knockdown of VRK1 in VRK2-null or VRK2-methylated cells results in decreased activity of the downstream substrate Barrier to Autointegration Factor (BAF), a regulator of post-mitotic nuclear envelope formation. VRK1 knockdown, and thus reduced BAF activity, causes nuclear lobulation, blebbing and micronucleation, which subsequently results in G2/M arrest and DNA damage. The VRK1-VRK2 synthetic lethal interaction is dependent on VRK1 kinase activity and is rescued by ectopic VRK2 expression. Knockdown of VRK1 leads to robust tumor growth inhibition in VRK2-methylated GBM xenografts. These results indicate that inhibiting VRK1 kinase activity could be a viable therapeutic strategy in VRK2-methylated GBM.

cancer biology↗

bioRxiv2021

Distinct cell adhesion signature defines glioblastoma myeloid-derived suppressor cell subsets

Increased myeloid-derived suppressor cell (MDSC) frequency is associated with worse outcomes and poor therapeutic response in glioblastoma (GBM). Monocytic (m) MDSCs represent the predominant subset in the GBM microenvironment. However, the molecular basis of mMDSC enrichment in the tumor microenvironment compared to granulocytic (g) MDSCs has yet to be determined. Here, we report that mMDSCs and gMDSCs display differences in their tumoraccelerating ability, with mMDSCs driving tumor growth in GBM models. Epigenetic assessments indicate enhanced gene accessibility for cell adhesion programs in mMDSCs and higher cellsurface integrin expression in mouse and human mMDSCs. Integrin {beta}1 blockage abrogated the tumor-promoting phenotype of mMDSCs and altered the immune profile in the tumor microenvironment. These findings suggest that integrin {beta}1 expression underlies the enrichment of mMDSCs in tumors and represents a putative immunotherapy target to attenuate myeloid cell-driven immune suppression in GBM. SummaryMyeloid-derived suppressor cells (MDSCs) drive glioblastoma growth; however, the function of specific MDSCs subsets is unclear. Bayik et al. demonstrate that adhesion programs are enhanced in monocytic MDSCs and responsible for their GBM-promoting function.

immunology↗

bioRxiv2021

Targeting the Cx26/NANOG/Focal Adhesion Kinase Complex via Cell Penetrating Peptides in Triple Negative Breast Cancers

Triple-negative breast cancer (TNBC) represents the most lethal and treatment-resistant breast cancer subtype with limited treatment options. We previously identified a protein complex unique to TNBC cancer stem cells composed of the gap junction protein connexin 26 (Cx26), the pluripotency transcription factor NANOG, and focal adhesion kinase (FAK). We sought to determine whether a peptide mimetic of Cx26 designed to target the complex attenuated tumor growth in pre-clinical models. Histological assessment was employed to verify expression of complex members. We designed peptides based on Cx26 juxtamembrane domains and performed binding experiments with NANOG and FAK using surface plasmon resonance. Peptides with high affinity were engineered with a cell-penetrating sequence and assessed in functional assays including cell proliferation, self-renewal, and in vivo tumor growth, and downstream signaling changes were measured. Binding studies revealed that the Cx26 C-terminal tail and intracellular loop bound to NANOG and FAK with submicromolar-to-micromolar affinity and that a 5-amino acid sequence in the C-terminal tail of Cx26 (RYCSG) was sufficient for binding. The Cx26 C-terminal tail was tagged with an antennapedia cell-penetrating peptide sequence and intracellular localization was confirmed. The cell-penetrating Cx26 peptide (aCx26-pep) disrupted self-renewal as assessed by tumorsphere formation assay while reducing nuclear FAK and NANOG and inhibiting NANOG target gene expression in TNBC cells but not luminal mammary epithelial cells. In vivo, aCx26-pep reduced tumor growth and proliferation and induced cell death. We provide proof-of-concept that a Cx26 peptide-based strategy inhibits growth and alters NANOG activity in TNBC.

cancer biology↗

bioRxiv2021

Lymphocyte-specific Protein Tyrosine Kinase Regulates Homologous Recombination (HR) DNA Repair and Targeting Enhances PARPi Utility in HR Proficient Ovarian Cancer

Poly-ADP Ribose Polymerase (PARP) targeted therapy is clinically approved for the treatment of homologous recombination (HR) repair deficient tumors. The remarkable success in treatment of HR repair deficient cancers has not translated to HR-proficient cancer. Our studies identify the mechanism of non-receptor lymphocyte-specific protein tyrosine kinase (LCK) in HR repair in endometrioid epithelial ovarian cancer (eEOC). LCK expression is induced and activation in the nucleus in response to DNA damage insult. LCK inhibition attenuates expression of RAD51, BRCA1, and BRCA2 proteins necessary for HR-mediated DNA repair, sufficient to suppress RAD51 foci formation, and augments {gamma}H2AX foci formation. Mechanistically, DNA damage leads to direct interaction of LCK with RAD51 and BRCA1 in a kinase dependent manner. Attenuation of LCK sensitized HR-proficient eEOC cells to PARP inhibitor in cell culture and pre-clinical mouse studies. These findings identify a new mechanism for expanding utility of PARP inhibitors in HR proficient ovarian cancer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/433791v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1715c60org.highwire.dtl.DTLVardef@167cb5forg.highwire.dtl.DTLVardef@158d807org.highwire.dtl.DTLVardef@1ced201_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2020

Multimodal Single-Cell Omics Analysis of COVID-19 Sex Differences in Human Immune Systems

Sex differences in the risk of SARS-CoV-2 infection have been controversial and the underlying mechanisms of COVID-19 sexual dimorphism remain understudied. Here we inspected sex differences in SARS-CoV-2 positivity, hospitalization, admission to the intensive care unit (ICU), sera immune profiling, and two single-cell RNA-sequencing (snRNA-seq) profiles from nasal tissues and peripheral blood mononuclear cells (PBMCs) of COVID-19 patients with varying degrees of disease severity. Our propensity score-matching observations revealed that male individuals have a 29% increased likelihood of SARS-CoV-2 positivity, with a hazard ration (HR) 1.32 (95% confidence interval [CI] 1.18-1.48) for hospitalization and HR 1.51 (95% CI 1.24-1.84) for admission to ICU. Sera from male patients at hospital admission had decreased lymphocyte count and elevated inflammatory markers (C-reactive protein, procalcitonin, and neutrophils). We found that SARS-CoV-2 entry factors, including ACE2, TMPRSS2, FURIN and NRP1, have elevated expression in nasal squamous cells from males with moderate and severe COVID-19. Cell-cell network proximity analysis suggests possible epithelium-immune cell interactions and immune vulnerability underlying a higher mortality in males with COVID-19. Monocyte-elevated expression of Toll like receptor 7 (TLR7) and Bruton tyrosine kinase (BTK) is associated with severe outcomes in males with COVID-19. These findings provide basis for understanding immune responses underlying sex differences, and designing sex-specific targeted treatments and patient care for COVID-19.

systems biology↗

bioRxiv2020

LPA/PKD-1 signaling promotes development of arteriolar niche that supports self-renewal of breast cancer stem cells and stemness

Breast cancer stem cells (BCSCs) are essential for cancer growth, metastasis and recurrence. However, the regulatory mechanisms of self-renewal and interactions with the vascular niche within tumor microenvironment are currently under investigation. Here, we demonstrate that BCSCs are enriched within arteriolar niche within the tumor microenvironment of estrogen receptor positive (ER+) BC and bi-directionally interact with arteriolar endothelial cells (ECs). Mechanistically, this interaction is driven by the LPA/PKD-1 signaling pathway, which promotes arteriolar differentiation and self-renewal. Furthermore, this pathway directly promotes stemness features. These findings suggest that targeting LPA/PKD-1 signaling may disrupt the arteriolar niche within the tumor microenvironment and concomitantly eradicate BCSCs, thereby attenuating BC progression.

cancer biology↗

bioRxiv2020

Single-Cell Analysis of Hyperthermic Intraperitoneal Chemotherapy Treated Tumors Reveals Distinct Cellular and Molecular Responses

Hyperthermic intraperitoneal chemotherapy (HIPEC) has emerged as a clinical regimen that prolongs overall survival for patients with advanced Epithelial Ovarian Cancer (EOC). However, the mechanism of action of HIPEC remains poorly understood. To provide insights into the rapid changes that accompany HIPEC, tumors from five patients with high grade serous ovarian cancer were harvested from the omentum at time of debulking and after 90 minutes of HIPEC treatment. Specimens were rapidly dissociated into single cells and processed for single cell RNA-seq. Unbiased clustering identified 19 cell clusters that were annotated based on cellular transcriptome signatures to identify the epithelial, stromal, T and B immune cells, macrophages, and natural killer cell populations. Hallmark pathway analysis revealed heat shock, metabolic reprogramming, inflammatory, and EMT pathway enrichment in distinct cell populations upon HIPEC treatment. Collectively, our findings provide the foundation for mechanistic studies focused on how HIPEC orchestrates the ovarian cancer tissue response.

cancer biology↗

bioRxiv2020

Multimodal single-cell/nucleus RNA-sequencing data analysis uncovers molecular networks between disease-associated microglia and astrocytes with implications for drug repurposing in Alzheimer's disease

Systematic identification of molecular networks in disease relevant immune cells of the nervous system is critical for elucidating the underlying pathophysiology of Alzheimers disease (AD). Two key immune cell types, disease-associated microglia (DAM) and disease-associated astrocytes (DAA), are biologically involved in AD pathobiology. Therefore, uncovering molecular determinants of DAM and DAA will enhance our understanding of AD biology, potentially identifying novel therapeutic targets for AD treatment. Here, we present an integrative, network-based methodology to uncover conserved molecular networks between DAM and DAA. Specifically, we leverage single-cell and single-nucleus RNA sequencing data from both AD transgenic mouse models and AD patient brains, drug-target networks, metabolite-enzyme associations, and the human protein-protein interactome, along with large-scale patient data validation from the MarketScan Medicare Supplemental Database. We find that common and unique molecular network regulators between DAM (i.e, PAK1, MAPK14, and SYK) and DAA (i.e., NFKB1, FOS, and JUN) are significantly enriched by multiple neuro-inflammatory pathways and well-known genetic variants (i.e., BIN1) from genome-wide association studies. Further network analysis reveal shared immune pathways between DAM and DAA, including Fc gamma R-mediated phagocytosis, Th17 cell differentiation, and chemokine signaling. Furthermore, integrative metabolite-enzyme network analyses imply that fatty acids (i.e., elaidic acid) and amino acids (i.e., glutamate, serine, and phenylalanine) may trigger molecular alterations between DAM and DAA. Finally, we prioritize repurposed drug candidates for potential treatment of AD by agents that specifically reverse dysregulated gene expression of DAM or DAA, including an antithrombotic anticoagulant triflusal, a beta2-adrenergic receptor agonist salbutamol, and the steroid medications (fluticasone and mometasone). Individuals taking fluticasone (an approved anti-inflammatory and inhaled corticosteroid) displayed a significantly decreased incidence of AD (hazard ratio (HR) = 0.858, 95% confidence interval [CI] 0.829-0.888, P < 0.0001) in retrospective case-control validation. Furthermore, propensity score matching cohort studies also confirmed an association of mometasone with reduced incidence of AD in comparison to fluticasone (HR =0.921, 95% CI 0.862-0.984, P < 0.0001).

neuroscience↗