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bioRxiv2025

EWS-FLI1 Expression in Human Embryonic MSCs Leads to Transcriptional Reprograming, Defective DNA Damage Repair and Ewing Sarcoma

Ewing sarcoma (ES) is an aggressive bone and soft tissue neoplasm characterized by EWSR1/ETS rearrangements and whose cellular origin remains unclear. EWS-FLI1 expression in human pediatric mesenchymal stem cells (hpMSCs) induces a quantitatively and qualitatively different transcriptional response than its expression in human adult MSCs (haMSCs), but fails to form tumors in vivo. ES cells have early developmental lineage signatures distinct from postnatal MSCs. Here, we have generated MSCs from experimental teratomas out of human embryonic stem cells (heSCs). Transduction of these human embryonic mesenchymal stem cells (heMSCs) with EWS-FLI1 results in the acquisition of an ES transcriptome, although the oncogene does not preferentially bind to promoters, but to intronic and intergenic microsatellites with >10 CA dinucleotides and GGAA repeats, respectively. In heMSCs, EWS-FLI1 directly regulates BRCA1 expression, although EWS-FLI1-expressing cells show defects in DNA damage repair. Xenografting of EWS-FLI1-transduced heMSCs resulted in the formation of tumors expressing characteristic ES markers. In summary, EWS-FLI1 enforces an aberrant transcriptome and endows in vivo transforming capacity when expressed in an undifferentiated early heMSC. Our approach represents an innovative experimental method for understanding critical aspects of the biology of developmental tumors, from leukemia to sarcomas, in which few (even single) genetic alterations are able to transform a fetal stem cell.

cancer biology↗

bioRxiv2022

CAR-T Engager Proteins Optimize Anti-CD19 CAR-T Cell Therapies for Lymphoma

B cell lymphoma therapy has been transformed by CD19-targeting cellular therapeutics that induce high clinical response rates and impressive remissions in relapsed and refractory patients. However, approximately half of all patients who respond to CD19-directed cell therapy relapse, the majority within six months. One characteristic of relapse is loss or reduction of CD19 expression on malignant B cells. We designed a unique therapeutic to prevent and reverse relapses due to lost or reduced CD19 expression. This novel biologic, a CAR T Engager, binds CD20 and displays the CD19 extracellular domain. This approach increases the apparent CD19 antigen density on CD19-positive/CD20-positive lymphoma cells, and prevents CD19 antigen-oss induced relapse, as CD19 bound to CD20 remains present on the cell surface. We demonstrate that this novel therapeutic prevents and reverses lymphoma relapse in vitro and prevents CD19-negative lymphoma growth and relapse in vivo.

cancer biology↗

bioRxiv2023

Deep intravital brain tumor imaging enabled by tailored three-photon microscopy and analysis

Intravital two-photon microscopy has emerged as a powerful technology to study brain tumor biology and its temporal dynamics, including invasion, proliferation and therapeutic resistance in the superficial layers of the mouse cortex. However, intravital microscopy of deeper cortical layers and especially the subcortical white matter, an important route of glioblastoma invasion and recurrence, has not yet been feasible due to low signal-to-noise ratios, missing spatiotemporal resolution and the inability to delineate myelinated axonal tracts. Here, we present a tailored intravital microscopy and artificial intelligence-based analysis methodology and workflow that enables routine deep imaging of glioblastoma over extended time periods, named Deep3P. We show that three-photon microscopy, adaptive optics, as well as customized deep learning-based denoising and machine learning segmentation together allow for deep brain intravital investigation of tumor biology up to 1.2 mm depth. Leveraging this approach, we find that perivascular invasion is a preferred invasion route into the corpus callosum as compared to intracortical glioblastoma invasion and uncover two vascular mechanisms of glioblastoma migration in the white matter. Furthermore, we can define an imaging biomarker of white matter disruption during early glioblastoma colonization. Taken together, Deep3P allows for an efficient and non-invasive investigation of brain tumor biology and its tumor microenvironment in unprecedented deep white and gray matter of the living mouse, opening up novel opportunities for studying the neuroscience of brain tumors and other model systems.

cancer biology↗

bioRxiv2018

Molecular phenotyping using networks, diffusion, and topology: soft tissue sarcoma

Many biological datasets are high-dimensional yet manifest an underlying order. In this paper, we describe an unsupervised data analysis methodology that operates in the setting of a multivariate dataset and a network which expresses influence between the variables of the given set. The technique involves network geometry employing the Wasserstein distance, global spectral analysis in the form of diffusion maps, and topological data analysis using the Mapper algorithm. The prototypical application is to gene expression profiles obtained from RNA-Seq experiments on a collection of tissue samples, considering only genes whose protein products participate in a known pathway or network of interest. Employing the technique, we discern several coherent states or signatures displayed by the gene expression profiles of the sarcomas in the Cancer Genome Atlas along the p53 signaling network. The signatures substantially recover the leiomyosarcoma, dedifferentiated liposarcoma (DDLPS), and synovial sarcoma histological subtype diagnoses, but they also include a new signature defined by simultaneous activation and inactivation of about a dozen genes, including activation of fibrinolysis inhibitor SERPINE1/PAI and inactivation of p53-family tumor suppressor gene P73 along with cyclin dependent kinase inhibitor 2A CDKN2A/P14ARF.

cancer biology↗

bioRxiv2021

Micro-region transcriptomics of fixed human tissue using Pick-Seq

Spatial transcriptomics and multiplexed imaging are complementary methods for studying tissue biology and disease. Recently developed spatial transcriptomic methods use fresh-frozen specimens but most diagnostic specimens, clinical trials, and tissue archives rely on formaldehyde-fixed tissue. Here we describe the Pick-Seq method for deep spatial transcriptional profiling of fixed tissue. Pick-Seq is a form of micro-region sequencing in which small regions of tissue, containing 5-20 cells, are mechanically isolated on a microscope and then sequenced. We demonstrate the use of Pick-Seq with several different fixed and frozen human specimens. Application of Pick-Seq to a human melanoma with complex histology reveals significant differences in transcriptional programs associated with tumor invasion, proliferation, and immuno-editing. Parallel imaging confirms changes in immuno-phenotypes and cancer cell states. This work demonstrates the ability of Pick-Seq to generate deep spatial transcriptomic data from fixed and archival tissue with multiplexed imaging in parallel.

cancer biology↗

bioRxiv2021

METTL9 regulates N1-histidine methylation of zinc transporters to promote tumor growth

Methyltransferase like 9 (Mettl9) is a member of the methyltransferase like protein family which is characterized by the presence of binding domains for S-adenosyl methionine, (SAM), a co-substrate for methylation reactions. Despite METTL9 is predicted to be a methyltransferase, its enzymatic activity, substrate specificities and biological functions are still poorly characterized. In this study, we revealed a tumor-promoting role for METTL9. We found that deletion of Mettl9 in tumor cells suppresses tumor growth and elicits potent anti-tumor immunity. Mechanistically, METTL9 is a N1-histidine methyltransferase which methylates the histidine residues of a x-His-x-His (xHxH) motif on the substrates. This motif is found extensively in zinc transporter families SLC39s and SLC30s, particularly in SLC39A7. Deletion of Mettl9 impairs cytoplasmic zinc homeostasis, resulting in an altered gene expression program with increased endoplasmic reticulum (ER) stress and reduced cell cycle. Mutation of key METTL9 catalyzed methylhistidine residues of SLC39A7 impairs cytoplasmic zinc homeostasis and affects cell growth as well. Notably, METTL9 expression is increased in some cancer types and its higher expression is associated with worse clinical outcomes, particularly in liver and pancreatic cancer. In summary, our work identified METTL9 as a potential new oncogene and its mediated methylation is of regulatory importance. Identifying selective and potent small-molecule inhibitors of METTL9 could thus represent novel therapeutic strategy for anti-proliferative cancer drugs.

cancer biology↗

bioRxiv2023

Novel loading protocol combines highly efficient encapsulation of exogenous therapeutic toxin with preservation of extracellular vesicles properties, uptake and cargo activity

Extracellular vesicles (EVs) have mostly been investigated as carriers of biological therapeutics such as proteins and RNA. Nevertheless, small-molecule drugs of natural or synthetic origin have also been loaded into EVs, resulting in an improvement of their therapeutic properties. A few methods have been employed for EV cargo loading, but poor yield and drastic modifications of vesicles remain unsolved challenges. We tested a different strategy based on temporary pH alteration through incubation of EVs with alkaline sodium carbonate, which resulted in conspicuous exogenous molecule incorporation. In-depth characterization showed that vesicle size, morphology, composition, and uptake were not affected. Our method was more efficient than gold-standard electroporation, particularly for a potential therapeutic toxin: the plant Ribosome Inactivating Protein saporin. The encapsulated saporin resulted protected from degradation, and was efficiently conveyed to receiving cancer cells and triggered cell death. EV-delivered saporin was more cytotoxic compared to the free toxin. This approach allows both the structural preservation of vesicle properties and the transfer of protected cargo in the context of drug delivery.

cancer biology↗

bioRxiv2025

SIRT2, TFEB, CNIH3, ADRM1, AND TM9SF4 AS POTENTIAL BIOMARKERS OF RESISTANCE TO CRIZOTINIB AND POOR PROGNOSIS IN LUNG ADENOCARCINOMA: IMPLICATIONS FOR TARGETED THERAPY AND IMMUNOTHERAPY

BackgroundLung adenocarcinoma (LUAD) with ALK mutations benefits from targeted treatment with ALK tyrosine kinase inhibitors, such as crizotinib. This therapy has been shown to be more effective than traditional chemotherapy, with improved tolerance in patients. However, resistance to crizotinib can develop, limiting its long-term efficacy. The aim of this study is to identify deregulated genes in crizotinib-resistant ALK-mutated lung adenocarcinoma cell lines. This will allow us to select patients who are more likely to benefit from crizotinib and help design new therapeutic strategies to overcome resistance, ultimately leading to better clinical outcomes. MethodsAn in silico study using genomic data from crizotinib-sensitive and crizotinib-resistant LUAD cells was conducted. Through statistical analysis, genes with differential expression in crizotinib resistant cells were identified. These genes were classified by their biological function using Enrichr, and those with the highest amplification frequency according to cBIOPORTAL were selected. Next, gene expression association with prognosis and with immune cell infiltration were investigated using Kaplan-Meier plotter and TIMER databases, respectively. Gene expression analysis in normal and tumoral tissues was explored using TNM plot and potential therapeutic agents against the identified targets were identified from several databases. ResultsWe found 9 genes overexpressed in resistant LUAD cells, with statistically significant cell function, to be amplified and associated with poor prognosis. Among them, SIRT2, TFEB, TMPSF4, CINH3 and ADRM1 display an immunosuppressed TME and TMPSF4, CINH3 and ADRM1 are overexpressed in tumoral tissue. Some of them, such as SIRT2, have therapeutic agents already approved in other context (gefitinib in EFGR mutated lung cancer). We identified nine genes that are overexpressed in crizotinib-resistant cell lines and are associated with poor prognosis. Additionally, we observed differences in immune infiltration patterns based on the specific overexpressed gene. These findings suggest potential avenues for therapeutic intervention, such as the use of combination therapies with crizotinib, including immunotherapy or targeted therapies aimed at resistance pathways. These strategies could enhance treatment efficacy in tumors expressing these genes. ConclusionsSIRT2, TFEB, TM9SF4, CINH3, and ADRM1 are potential biomarkers for crizotinib-resistant and worse prognosis in LUAD. Our findings provide valuable insights into the mechanisms of crizotinib resistance and potential avenues for therapeutic intervention. HighlightsO_LIIn silico analysis identified nine overexpressed genes in crizotinib-resistant lung adenocarcinoma cell lines, all associated with worse prognosis. C_LIO_LITumor levels of SIRT2, TFEB, TM9SF4, CINH3, and ADRM1 correlate with higher infiltration of immunosuppressive populations and, the last three, with lower infiltration of immune-promoting cells. C_LIO_LIThese genes are potentially druggable targets in the context of crizotinib resistance, with existing treatments that could be explored. C_LIO_LIThe tumor microenvironment (TME) may play a significant role in these tumors, suggesting that immunotherapy could be a viable treatment option in this setting. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/662953v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@16075ecorg.highwire.dtl.DTLVardef@1de1942org.highwire.dtl.DTLVardef@4c60eaorg.highwire.dtl.DTLVardef@6ec6b4_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2019

DNA hydroxymethylation reveals transcription regulation networks and prognostic signatures in multiple myeloma

Multiple myeloma (MM) is a plasma cell malignancy that remains challenging to cure despite a substantially improving median survival. During the last decade, DNA copy number variation and gene expression studies have described the pathology and its heterogeneity among patients. Epigenetic modifications play important roles in MM, but they are rarely associated with clinical aspects of the disease. In this epigenomics study, we produced quantifications of genomic 5-methylcytosine (5mC) and of 5-hydroxymethylcytosine (5hmC) as well as genome-wide maps of hydroxymethylation to analyse myeloma cells taken from a cohort of 40 newly diagnosed and homogeneously treated patients. We found 5hmC to be globally depleted in MM compared to normal plasma cells, as well as being reduced in advanced clinical stages of the disease. From the hydroxymethylome data, we observed that remaining 5hmC is organised in large peak clusters and is associated with well-known disease-related genes. Based on their signal correlation, these 5hmC peak clusters can be gathered in 2 regulation networks involving core transcription factors such as IRF4, MYC, PRDM1 and TCF3. By performing paired hydroxymethylomes at diagnosis and at relapse, we found the disease progression to be heterogeneous and patient-specific. We found that the location of 5hmC at tumor suppressor TP53INP1 is associated with better outcome while global high level of 5hmC tends to be associated with better overall survival. Together, our study suggests that 5hmC provides new biological insights of the disease severity and progression, and can be used for retrospective studies.\n\nKey PointsO_LI5hmC is globally depleted in MM and even more in advanced stages of the disease.\nC_LIO_LI5hmC is locally detected at transcriptionally active regions of MM where its presence can be associated with survival.\nC_LI

cancer biology↗

bioRxiv2019

Degradation of Polycomb Repressive Complex 2 with an EED-targeted Bivalent Chemical Degrader

Protein degradation via the use of bivalent chemical degraders provides an alternative strategy to block protein function and assess the biological roles of putative drug targets. This approach capitalizes on the advantages of small molecule inhibitors while moving beyond the restrictions of traditional pharmacology. Herein we report a first-in-class chemical degrader (UNC6852) that targets Polycomb Repressive Complex 2 (PRC2). UNC6852 contains an EED226 derived ligand and a ligand for VHL which bind to the WD40 aromatic cage of EED and CRL2VHL, respectively, to induce proteasomal degradation of PRC2 components, EED, EZH2, and SUZ12. Degradation of PRC2 with UNC6852 blocks the histone methyltransferase activity of EZH2, decreasing H3K27me3 levels in HeLa cells and diffuse large B-cell lymphoma (DLBCL) cells containing an EZH2Y641N gain-of-function mutation. UNC6852 degrades both wild type EZH2 and EZH2Y641N, and additionally displays anti-proliferative effects in this cancer model system.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC=\"FIGDIR/small/676965v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (34K):\norg.highwire.dtl.DTLVardef@5b8f01org.highwire.dtl.DTLVardef@1098ff7org.highwire.dtl.DTLVardef@caa1a9org.highwire.dtl.DTLVardef@13b6bfc_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Glioblastoma states are defined by cohabitating cellular populations with progression-, imaging- and sex-distinct patterns

Background: Magnetic Resonance Imaging (MRI) is the mainstay for neurosurgical oncology but not for informing us about glioma biology. An obstacle to developing MR-based glioma biomarkers is the absence of rigorous correlation between MRI features and glioma biology as assessed in multi-regional biopsies, within and across patients. Methods: We directly addressed this obstacle by collating a unique cohort of 202 MRI-localized biopsies from 58 patients. We define a low-dimensional transcriptional pseudotime continuum along which heterogeneous high-grade glioma (HGG) samples organize both within and across patients. Results: We observe three polarized transcriptional tissue states: infiltrated brain, immune/inflammatory, and proliferative associated with patterns of cohabitation of cellular subpopulations. The states and deconvolved populations show correlation with enhancement status on T1Gd MRI. Moreover, discrete MRI habitats, regions sharing common imaging features, defined as combinations of high or low signal intensity across multiparametric MRI revealed 14 MRI habitats. We order the MRI habitats according to the average pseudotime on the transcriptional continuum. We find that MRI habitats with low pseudotime (associated with early tumor development and diffusely invaded brain tissue) localized at the periphery of the tumor whilst high pseudotime either proliferative or immune/inflammatory states were towards the core of the lesion. We find that composition of MRI habitats is impacted by MGMT status. Conclusion: This suggests that ongoing aggregation of MRI-localized biopsies may augment our projection of biology onto MRI habitats to support the noninvasive identification of cellular ecologies within and across each patient's tumor.

cancer biology↗

bioRxiv2023

Integrated analysis of canine soft tissue sarcomas identifies recurrent mutations in TP53, KMT genes and PDGFB fusions

Canine soft tissue sarcomas (STS) are a heterogenous group of malignant tumors arising from mesenchymal cells of soft tissues. This simplified collective of tumors most commonly arise from subcutaneous tissues, are treated similar clinically, and conventionally exclude other sarcomas with more definitive anatomical, histological, or biological features. Histologically, canine STS sub-types are difficult to discern at the light microscopic level due to their overlapping features. Thus, genomic, and transcriptomic profiling of canine STS may prove valuable in differentiating the diverse sub-types of mesenchymal neoplasms within this group. To this purpose we sought to characterize the transcript expression and genomic mutation profiles of canine STS. To delineate transcriptomic sub-types, hierarchical clustering was used to identify 4 groups with district expression profiles. Using the RNAseq data, we identified three samples carrying driver fusions of platelet derived growth factor B (PDGFB) and collagen genes. Sensitivity to imatinib was evaluated in a canine STS cell line also bearing a PDGFB fusion. Using whole exome sequencing, recurrent driver variants were identified in the cancer genes KMT2D (21% of the samples) and TP53 (21%) along with copy number losses of RB1 and CDKN2A. Gene amplifications and resulting transcript increases were identified in genes on chromosomes 13, 14, and 36. A subset of STS was identified with high T-cell infiltration. This multi-omics approach has defined canine STS sub-types at a molecular level for comparison to their human counterparts, to improve diagnosis, and may provide additional targets for therapy.

cancer biology↗

bioRxiv2026

Clone-level multi-modal prediction of tumour drug response

Tumour heterogeneity presents a major challenge for precision oncology, as genetically and phenotypically distinct tumour clones may respond differently to therapy. To address this, we introduce scClone2DR, a probabilistic multi-modal framework that predicts drug responses at the level of individual tumour clones by integrating single-cell DNA and RNA sequencing with ex-vivo drug-screening data. In simulations, scClone2DR substantially outperforms alternatives in recovering true drug-effects and clonal sensitivities. Applied to 60 melanoma and 21 acute myeloid leukaemia patient samples, the method identifies heterogeneous clonal responses, yields biologically meaningful feature rankings, highlights clones that may be resistant to treatment, and improves the prediction of clinical outcomes compared to models ignoring clonal structure. These results demonstrate that modelling tumour evolution and clonal diversity is crucial for accurate drug-response prediction and provides a foundation for more effective, clone-aware precision oncology.

cancer biology↗

bioRxiv2026

Accurate somatic variant detection from formalin fixed, paraffin embedded tissue (FFPE) derived WES and WGS by DeepOmicsFFPE-PLUS, a sequence context-based transformer

Formalin-fixed paraffin-embedded (FFPE) tissues represent a vast archival resource for genomic studies, yet their utility remains constrained by fixation-induced DNA damage and subsequent sequencing artifacts. To comprehensively characterize and address this challenge, we analyzed matched FFPE and fresh-frozen tumor samples from two institutions, spanning different storage durations, DNA qualities, sequencing platforms (WES and WGS), exome capture kits, and somatic variant callers. We found that FFPE-induced artifacts exhibit strong batch- and age-specific patterns, with a predominance of C:G>T:A substitutions, which particularly complicate the accurate identification of low allele frequency true variants. Enzymatic repair methods partially alleviated these artifacts but remained insufficient. To overcome these limitations, we developed DeepOmicsFFPE-PLUS(https://github.com/Theragen-Bio/DeepOmicsFFPE-PLUS), an advanced AI-based tool to accurately distinguish true somatic variants from FFPE-specific artifacts. DeepOmicsFFPE-PLUS demonstrated consistently superior performance across diverse conditions, achieving high sensitivity and specificity--even for low-frequency variants--outperforming existing tools. Application of our model to WGS data further enabled recovery of biologically relevant mutational signatures, including restoration of microsatellite instability (MSI)-associated signatures initially obscured by FFPE artifacts. Our findings underscore the necessity of artifact-aware variant calling in FFPE genomics and establish DeepOmicsFFPE-PLUS as a robust tool for artifact removal, enabling high-fidelity downstream analyses and personalized therapeutic target discovery.

cancer biology↗

bioRxiv2022

Spatial transcriptomic analysis of childhood ependymoma implicates unresolved wound healing as a driver of tumor progression

Childhood ependymoma (EPN) is a brain tumor that has seen limited improvements in outcome over past decades. The underlying cellular components of EPN have recently been revealed by single cell RNA-sequencing (scRNAseq), providing biological insights. Here we use spatial transcriptomics to comprehensively chart gene expression across the cellular landscape of posterior fossa subgroup A (PFA) EPN, the commonest and most deadly EPN variant, providing novel resolution of cellular heterogeneity and cellular interaction. We reveal that PFA are comprised of epithelial and mesenchymal histological zones each containing a diversity of cellular states. These include co-existing and spatially distinct undifferentiated progenitor-like clusters - a quiescent mesenchymal zone population, and a second highly mitotic progenitor population that is restricted to hypercellular epithelial zones. We show that myeloid cell interaction is the leading cause of mesenchymal transition in PFA, occurring in zones spatially distinct from hypoxia-induced mesenchymal transition, and these distinct EMT-initiating processes were replicated in in-vitro models of PFA. Collectively, our transcriptomic and functional analyses mirror the processes of normal wound healing where PFA mesenchymal and epithelial zones interact with immune subpopulations in cycle of persistent tissue damage response and mitogenic re-epithelialization signals. Spatial transcriptomics advances our understanding of PFA biology, implicating a "wound that will not heal" process as a driver of tumor progression, a new concept that could provide novel targets for effective therapeutic intervention. SignificanceSpatial transcriptomic analysis of the ependymoma tumor microenvironment identifies novel cell populations and interactions, implicating unresolved wound healing as a clinically actionable driver of tumor progression in this refractory childhood brain tumor.

cancer biology↗

bioRxiv2021

Crystal structures of the σ2 receptor template large-library docking for selective chemotypes active in vivo

The {sigma}2 receptor is a poorly understood transmembrane receptor that has attracted intense interest in many areas of biology including cancer imaging, Alzheimers disease, schizophrenia, and neuropathic pain. However, little is known regarding the molecular details of the receptor, and few highly selective ligands are available. Here, we report the crystal structure of the {sigma}2 receptor in complex with the clinical drug candidate roluperidone and the probe compound PB28. These structures, in turn, templated a large-scale docking screen of 490 million make-on-demand molecules. Of these, 484 compounds were synthesized and tested, prioritizing not only high-ranking docked molecules, but also those with mediocre and poor scores. Overall, 127 compounds with binding affinities superior to 1 M were identified, all in new chemotypes, 31 of which had affinities superior to 50 nM. Intriguingly, hit rate fell smoothly and monotonically with docking score. Seeking to develop selective and biologically active probe molecules, we optimized three of the original docking hits for potency and for selectivity, achieving affinities in the 3 to 48 nM range and to up to 250-fold selectivity vs. the {sigma}1 receptor. Crystal structures of the newly discovered ligands bound to the {sigma}2 receptor were subsequently determined, confirming the docked poses. To investigate the contribution of the {sigma}2 receptor in pain processing, and to distinguish it from the contribution of the {sigma}1 receptor, two potent {sigma}2-selective and one potent {sigma}1/{sigma}2 non-selective ligand were tested for efficacy in a mouse model of neuropathic pain. All three ligands demonstrated timedependent decreases in mechanical hypersensitivity in the spared nerve injury model, supporting a role for the {sigma}2 receptor in nociception, and a possible role for {sigma}1/{sigma}2 polypharmacology. This study illustrates the opportunities for rapid discovery of in vivo active and selective probes to study under-explored areas of biology using structurebased screens of diverse, ultra-large libraries following the elucidation of protein structures.

pharmacology and toxicology↗

bioRxiv2022

GBMdeconvoluteR accurately infers proportions of neoplastic and immune cell populations from bulk glioblastoma transcriptomics data

The biological and clinical impact of neoplastic and immune cell type ratios in the glioblastoma (GBM) tumour microenvironment is being realised. Characterising and quantifying cell types within GBMs at scale will facilitate a better understanding of the association between the cellular landscape and tumour phenotypes or clinical correlates. This study aimed to develop a tool that can deconvolute immune and neoplastic cells within the GBM tumour microenvironment from bulk RNA sequencing data. We developed an IDH wild-type (IDHwt) GBM specific single immune cell reference dataset, from four independent studies, consisting of B cells, T cells, NK cells, microglia, tumour associated macrophages, monocytes, mast and DC cells. We used this alongside an existing neoplastic single cell-type dataset consisting of astrocyte-like, oligodendrocyte- and neuronal-progenitor like and mesenchymal GBM cancer cells to create both marker and gene signature matrix-based deconvolution tools. We then applied single-cell resolution imaging mass cytometry (IMC) to ten IDHwt GBM samples, five paired primary and recurrent tumours, in parallel with these tools to determine which performed best. Marker based gene expression deconvolution using GBM tissue specific markers, which we have packaged as GBMdeconvoluteR, gave the most accurate results. The correlation between immune cell quantification by IMC and by GBMdeconvoluteR for primary IDHwt GBM samples was 0.52 (Pearsons P=7.8x10-3) and between neoplastic cell quantification by IMC and by GBMdeconvoluteR was 0.75 (Pearsons P=1.2x10-3). We applied GBMdeconvoluteR to bulk GBM RNAseq data from The Cancer Genome Atlas (TCGA) and were able to recapitulate recent findings from multi-omics single cell studies with regards associations between mesenchymal GBM cancer cells and both lymphoid and myeloid cells. Furthermore, we were able to expand upon this to show that these associations are stronger in patients with worse prognosis. GBMdeconvoluteR is accessible online at https://gbmdeconvoluter.leeds.ac.uk. Key pointsGBMdeconvoluteR is a glioblastoma-specific cellular deconvolution tool. When applied to bulk GBM RNAseq data, it accurately quantifies the neoplastic and immune cells in that tumour. It is available online at https://gbmdeconvoluter.leeds.ac.uk

cancer biology↗

bioRxiv2018

Chemical characterization, biological assessment and molecular docking studies of essential oil of Ocimum viride

Ocimum viride (family: Lamiaceae) is a medicinally important aromatic plant that grows widely in north western Himalayan range of Indian subcontinent. Essentials oils (EOs) and purified aromatic compounds derived from plants of genus Ocimum have long been used in traditional system of medicine to treat various chronic disorders. In this study we made an attempt to assess the chemical composition of essential oil (EO) obtained from Ocimum viride for potential antimicrobial and anticancer properties. Gas chromatography-mass spectrometry (GCMS) analysis revealed that EOs of aerial parts (leaves) of Ocimum viride contain high amounts of oxygenated monoterpenes, thymol and gamma terpinene. Notably, thymol (~50%) and {gamma}-terpinene (~18%) were identified as the most abundant components of the oil. EOs showed most prominent antibacterial effect against Bacillus subtilis and in silico molecular docking analyses of antibacterial action against bacterial cell wall of Bacillus subtilis showed interaction of thymol with Sec A protein of Bacillus subtilis (binding energy of -15 kcal/mol) with active site Lys284, Trp275, Leu269, Arg19, Glu277, pro270. While, in vitro cytotoxic effect of EO against six human cancer cell lines showed maximum effect with IC50 value of ~0.034 {+/-} 0.001L/ mL against HT-29 colon cancer cell line. DNA fragmentation analysis and cell cycle analysis revealed that EO inhibits the growth of HT-29 colon cancer cells probably through induction of unrepairable DNA damage and subsequent cell death. Taken together, our results indicate that EO possesses potent antimicrobial and anticancer properties, and may find applications in bacterial growth inhibition and cancer therapeutics.

cancer biology↗