Biology subjects

Holland, E. C.

Publications and source records attributed to Holland, E. C..

At least 19 recordsLinked to original sources

bioRxiv2026

Adenosylhomocysteinase drives epigenetic and metabolic reprogramming in ZFTA-RELA ependymoma

Supratentorial ependymomas (ST-EPNs) are aggressive pediatric brain tumors predominantly driven by the recurrent ZFTA-RELA fusion, an oncogenic chromatin regulator that establishes an aberrant transcriptional program. Although metabolic pathways modulate epigenetic regulation by controlling the availability of metabolic cofactors, how ZFTA-RELA coordinates metabolic reprogramming with epigenetic regulation is not well understood. Here, we show that ZFTA-RELA-positive ependymomas exhibit enhanced methionine dependency, elevated adenosyl homocysteinase (AHCY) expression, and epigenetically control aspartate metabolism for tumor growth. Mechanistically, ZFTA-RELA upregulates AHCY, increasing cellular methylation potential which promotes H3K4me3-dependent expression of CAD, the first enzyme complex of de novo pyrimidine biosynthesis, while simultaneously enforcing H3K27me3 mediated repression of ASNS, which encodes asparagine synthetase. Through this coordinated epigenetic program, aspartate utilization is directed toward pyrimidine biosynthesis while endogenous asparagine production is limited. Restricting S-adenosylmethionine availability or genetically or pharmacologically inhibiting AHCY reverses these epigenetic states, leading to CAD downregulation, ASNS upregulation, impaired nucleotide synthesis, and suppression of tumor growth in vitro and in vivo. Similarly, EZH2 inhibition also restores ASNS expression and suppresses tumor proliferation. These findings suggest that ZFTA-RELA EPN maintain ASNS-low phenotype which conditionally make them dependent on extracellular asparagine. We further show that enhanced de novo pyrimidine synthesis not only supports nucleotide production but also provides UDP-sugars required for N-glycosylation and stabilization of the asparagine transporter SLC1A5, thereby promoting extracellular asparagine uptake and tumor proliferation. Collectively, our findings identify AHCY as a critical metabolic regulator of epigenetic and metabolic reprogramming that drives pyrimidine synthesis and establishes extracellular asparagine dependency, revealing actionable metabolic vulnerabilities in ZFTA-RELA-positive ST-EPNs.

cancer biology↗

bioRxiv2026

Transcriptomic analysis reveals differential regulation of synaptic components in pediatric and adult brain tumors

Neuronal-cancer cell interactions are a key component of brain tumor pathophysiology, yet many fundamental questions remain unanswered, with even more remaining unasked. Here, we present a comprehensive brain tumor reference map generated from bulk RNA-seq data of ~4,300 adult and pediatric brain tumors, including various glioma subtypes, medulloblastomas, ependymomas, and meningiomas, alongside ~1,400 healthy brain samples. By analyzing synaptic processes and synaptic gene expression across tumor types, we reveal the complexity of neuron-tumor crosstalk and its potential impact on patient survival. Our findings identify key synaptic signaling pathways and dysregulated patterns in brain tumors, including HNRNPH2 upregulation, a key factor in RNA processing and metabolism, in gliomas and medulloblastomas. Additionally, we highlight the role of cholinergic signaling, particularly CHRNA9, as a driver of glioma progression, which is also upregulated in WNT and Group 4 medulloblastomas, ependymomas, and meningiomas. Furthermore, P2 purinergic signaling emerges as a key player in glioma progression. These insights lay the groundwork for future studies exploring whether targeting these pathways could reprogram the tumor microenvironment toward an anti-tumor state, ultimately leading to novel therapeutic strategies and improved patient outcomes.

cancer biology↗

bioRxiv2026

A pan-cohort transcriptional landscape of breast cancer maps subtype and microenvironmental programs

Breast cancer comprises heterogeneous transcriptional states that are incompletely captured by discrete clinical or molecular subtype labels. To visualize this heterogeneity in a unified framework, we integrated bulk RNA-seq data from 2,284 patient samples across 13 studies using 18,089 protein coding genes, a harmonized processing pipeline, batch correction, consensus clustering and PaCMAP dimensionality reduction to construct an interactive breast cancer transcriptional landscape. Consensus clustering identified five major regions, which were annotated using PAM50 scores calculated for each sample: Luminal A, Luminal B, HER2 enriched, and two basal associated clusters. The basal clusters separated into an immune rich region marked by T cell-inflamed, tumor-associated macrophages (TAM), and low-purity signatures, and a cell-cycle driven region enriched for proliferation and DNA replication programs. Overlay of marker genes, pathways, kinases, neuronal like signaling programs, cancer associated fibroblasts (CAF) states, and TAM programs revealed spatially organized subtype biology and microenvironmental heterogeneity. Finally, projection of therapy associated resistance signatures identified landscape regions linked to predicted resistance to HER2-targeted therapy and hormone receptor directed endocrine therapies. By enabling interactive exploration of transcriptional states, marker genes, pathways, and therapeutic response programs, this resource provides a community framework for biomarker discovery in breast cancer.

bioinformatics↗

bioRxiv2026

Beyond Histology: A Unified Transcriptomic Atlas Defines Lung Cancer Biologic States and Subtypes

Lung cancer encompasses multiple histological entities with substantial molecular heterogeneity that remain incompletely resolved at population scale. Here, we constructed a unified reference landscape of lung cancer by analyzing raw RNA sequencing data from 1,824 tumors spanning adenocarcinoma (n=966), squamous cell carcinoma (n=628), small cell lung cancer (n=150), and unclassified non small cell lung cancer (n=80). Following batch correction, samples were analyzed using consensus clustering and visualized with PaCMAP to generate a molecular atlas annotated with clinical and biological metadata. Rather than segregating by pathological diagnosis, tumors organized along conserved transcriptional axes defined by tumor-intrinsic biology including proliferative or metabolic programs and immune-infiltrated states. Consensus clustering resolved nine robust molecular clusters, including an adenocarcinoma-associated subgroup, a neuroendocrine-like adenocarcinoma marked by ASCL1 activation, immune-associated regions, and bifurcation of both small cell and squamous carcinomas into biologically distinct states. Spatially restricted expression of selected clinically relevant transcripts nominated state-specific therapeutic hypotheses requiring future functional and clinical validation. Projection of patient tumors and patient-derived xenografts onto the atlas demonstrated preservation of transcriptional identity and enabled quantitative assessment of model fidelity. This integrated framework organizes lung cancer as a structured continuum of transcriptional states and provides a reference resource for biological interpretation and future translational studies.

bioinformatics↗

bioRxiv2025

Development of PROTACs for targeted degradation of oncogenic TRK fusions

Chromosomal translocations leading to the fusion of tropomyosin receptor kinases (TRK) with diverse partner proteins have been identified as oncogenic drivers in many adult and pediatric cancers. While first-generation TRK kinase inhibitors, such as entrectinib and larotrectinib, have shown positive responses in TRK fusion-positive cancers, resistance mutations against these inhibitors in the kinase domain limit their efficacy. Second-generation inhibitors are in clinical evaluation, highlighting a need for novel therapeutic modalities to achieve durable suppression of the oncogenic activity of TRK fusions. Here, we developed heterobifunctional small molecule degraders (PROTACs) to achieve targeted degradation of TRK fusions. By conjugating entrectinib to thalidomide, we identified JWJ-01-378 as a potent and selective CRBN-recruiting degrader of the TPM3-TRKA fusion. JWJ-01-378 induced TPM3-TRKA degradation through the ubiquitin-proteasome system and proteomics analysis confirmed the acute selectivity of JWJ-01-378 for achieving TPM3-TRKA degradation with minimal off-target effects. While JWJ-01-378 was also able to degrade wild-type TRK, it was unable to degrade TRK inhibitor resistant mutants and ALK fusions. Importantly, TPM3-TRKA degradation by JWJ-01-378 suppressed downstream signaling and reduced cancer cell viability, with improved responses compared to heterobifunctional control compounds that cannot degrade TPM3-TRKA. Together, our study expands the toolbox of compounds for evaluating targeted degradation of TRK fusions in cancer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=97 SRC="FIGDIR/small/660465v1_ufig13.gif" ALT="Figure 13"> View larger version (19K): org.highwire.dtl.DTLVardef@6c78f7org.highwire.dtl.DTLVardef@179dcdeorg.highwire.dtl.DTLVardef@1939988org.highwire.dtl.DTLVardef@144c718_HPS_FORMAT_FIGEXP M_FIG C_FIG JWJ-01-378 recruits cereblon (CRBN) to induce potent and selective degradation of oncogenic TRK fusions, leading to a collapse in downstream signaling and loss of cancer cell viability. Graphical abstract was created using Biorender.com.

cancer biology↗

bioRxiv2025

C-terminal fusion partner activity contributes to the oncogenic functions of YAP1::TFE3

YAP1 gene fusions are found in a multitude of human tumors, are potent oncogenic drivers, and are the likely initiating tumorigenic events in these tumors. We and others have previously shown that a YAP1 fusion proteins exert TEAD-dependent oncogenic YAP1 activity that is resistant to inhibitory Hippo pathway signaling. However, the contributions of the C-terminal fusion partners to the oncogenic functions of YAP1 fusion proteins are understudied. Here, we used the RCAS/tv-a system to express eight different YAP1 gene fusions in vivo and observed significant differences in the latencies of tumors induced by the various YAP1 fusions. We observed that tumors induced by YAP1::TFE3 displayed a significantly different histomorphology compared to tumors induced by other YAP1 fusions or activated non-fusion YAP1. To assess the extent to which the functional TFE3 domains (DNA binding: leucine zipper (LZ) and basic-helix-loop-helix (bHLH); activation domain (AD)) contribute to the oncogenic functions of YAP1::TFE3, we generated several mutant variants and performed functional in vitro and in vivo assays. In vitro, mutation or deletion of the TFE3 DNA binding domains (LZ, bHLH) resulted in reduced TFE3 activity but increased YAP1 activity of YAP1::TFE3. In vivo, deletion of the LZ and bHLH domains did not result in a decrease in tumor incidence but induced the formation of more YAP1-like tumors that lacked prominent features of YAP1::TFE3-driven tumors. By contrast, loss of the TFE3 AD almost completely abrogated tumor formation. Our results suggest that the TFE3 domains significantly contribute to the oncogenic activity of YAP1::TFE3.

cancer biology↗

bioRxiv2024

Aggressive high-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling via the upregulation of VGLL4 and FAT3/4.

Meningiomas are the most common primary brain tumors in adults. Although generally benign, a subset of meningiomas is of higher grade, shows aggressive growth behavior and recurs even after multiple surgeries. Around half of all meningiomas harbor inactivating mutations in NF2. While benign low-grade NF2 mutant meningiomas exhibit few genetic events in addition to NF2 inactivation, aggressive high-grade NF2 mutant meningiomas frequently harbor a highly aberrant genome. We and others have previously shown that NF2 inactivation leads to YAP1 activation and that YAP1 acts as the pivotal oncogenic driver in benign NF2 mutant meningiomas. Using bulk and single-cell RNA-Seq data from a large cohort of human meningiomas, we show that aggressive NF2 mutant meningiomas harbor decreased levels YAP1 activity compared to their benign counterparts. Decreased expression levels of YAP target genes are significantly associated with an increased risk of recurrence. We then identify the increased expression of the YAP1 competitor VGLL4 as well as the YAP1 upstream regulators FAT3/4 as a potential mechanism for the downregulation of YAP activity in aggressive NF2 mutant meningiomas. High expression of these genes is significantly associated with an increased risk of recurrence. In vitro, overexpression of VGLL4 resulted in the downregulation of YAP activity in benign NF2 mutant meningioma cells, confirming the direct link between VGLL4 expression and decreased levels of YAP activity observed in aggressive NF2 mutant meningiomas. Our results shed new insight on the biology of benign and aggressive NF2 mutant meningiomas and may have important implications for the efficacy of therapies targeting oncogenic YAP1 activity in NF2 mutant meningiomas.

molecular biology↗

bioRxiv2024

All-trans retinoic acid induces durable tumor immunity in IDH-mutant gliomas by rescuing transcriptional repression of the CRBP1-retinoic acid axis

Diffuse gliomas are epigenetically dysregulated, immunologically cold, and fatal tumors characterized by mutations in isocitrate dehydrogenase (IDH). Although IDH mutations yield a uniquely immunosuppressive tumor microenvironment, the regulatory mechanisms that drive the immune landscape of IDH mutant (IDHm) gliomas remain unknown. Here, we reveal that transcriptional repression of retinoic acid (RA) pathway signaling impairs both innate and adaptive immune surveillance in IDHm glioma through epigenetic silencing of retinol binding protein 1 (RBP1) and induces a profound anti-inflammatory landscape marked by loss of inflammatory cell states and infiltration of suppressive myeloid phenotypes. Restorative retinoic acid therapy in murine glioma models promotes clonal CD4+ T cell expansion and induces tumor regression in IDHm, but not IDH wildtype (IDHwt), gliomas. Our findings provide a mechanistic rationale for RA immunotherapy in IDHm glioma and is the basis for an ongoing investigator-initiated, single-center clinical trial investigating all-trans retinoic acid (ATRA) in recurrent IDHm human subjects.

cancer biology↗

bioRxiv2024

Development of a series of genetically engineered NTRK fusion-driven pediatric-type high-grade glioma mouse models

Pediatric-type high-grade gliomas frequently harbor gene fusions involving receptor tyrosine kinase genes, including neurotrophic tyrosine kinase receptor (NTRK) fusions. Clinically, these tumors show high initial response rates to tyrosine kinase inhibition but ultimately recur due to the accumulation of additional resistance-conferring mutations. Here, we developed a series of genetically engineered mouse models of treatment-naive and -experienced NTRK1/2/3 fusion-driven gliomas. Both the TRK kinase domain and the N-terminal fusion partners influenced tumor histology and aggressiveness. Treatment with TRK kinase inhibitors significantly extended survival of NTRK fusion-driven glioma mice in a fusion- and inhibitor-dependent manner, but tumors ultimately recurred due to the presence of treatment-resistant persister cells. Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools for preclinical testing of novel inhibitors and to study the cellular responses of NTRK fusion-driven gliomas to therapy.

cancer biology↗

bioRxiv2024

Direct measurement of RNA Polymerase II hypertranscription in cancer FFPE samples

Genome-wide hypertranscription is common in hu-man cancer and predicts poor prognosis. To under-stand how hypertranscription might drive cancer, we applied our FFPE-CUTAC method for mapping RNA Polymerase II (RNAPII) genome-wide in formalin-fixed paraffin-embedded (FFPE) sections. We demonstrate global RNAPII elevations in mouse gliomas and assort-ed human tumors in small clinical samples and discov-er regional elevations corresponding to de novo HER2 amplifications punctuated by likely selective sweeps. RNAPII occupancy at replication-coupled histone genes correlated with WHO grade in meningiomas, ac-curately predicted rapid recurrence, and corresponded to whole-arm chromosome losses. Elevated RNAPII at histone genes in meningiomas and diverse breast cancers is consistent with histone production being rate-limiting for S-phase progression and histone gene hypertranscription driving overproliferation and aneu-ploidy in cancer, with general implications for precision oncology.

cancer biology↗

bioRxiv2024

Meningioma transcriptomic landscape demonstrates novel subtypes with regional associated biology and patient outcome.

Meningiomas, the most common intracranial tumor, though mostly benign can be recurrent and fatal. WHO grading does not always identify high risk meningioma and better characterizations of their aggressive biology is needed. To approach this problem, we combined 13 bulk RNA-Seq datasets to create a dimension-reduced reference landscape of 1298 meningiomas. Clinical and genomic metadata effectively correlated with landscape regions which led to the identification of meningioma subtypes with specific biological signatures. Time to recurrence also correlated with the map location. Further, we developed an algorithm that maps new patients onto this landscape where nearest neighbors predict outcome. This study highlights the utility of combining bulk transcriptomic datasets to visualize the complexity of tumor populations. Further, we provide an interactive tool for understanding the disease and predicting patient outcome. This resource is accessible via the online tool Oncoscape, where the scientific community can explore the meningioma landscape.

cancer biology↗

bioRxiv2023

Rolling the evolutionary dice: Neisseria commensals as proxies for elucidating the underpinnings of antibiotic resistance mechanisms and evolution in human pathogens

Species within the genus Neisseria are especially adept at sharing adaptive allelic variation across species boundaries, with commensal species repeatedly transferring resistance to their pathogenic relative N. gonorrhoeae. However, resistance in commensal Neisseria is infrequently characterized at both the phenotypic and genotypic levels, limiting our ability to predict novel and potentially transferable resistance mechanisms that ultimately may become important clinically. Unique evolutionary starting places of each Neisseria species will have distinct genomic backgrounds, which may ultimately control the fate of evolving populations in response to selection, as epistatic and additive interactions may coerce lineages along divergent evolutionary trajectories. However alternatively, similar genetic content present across species due to shared ancestry may constrain the adaptive solutions that exist. Thus, identifying the paths to resistance across commensals may aid in characterizing the Neisseria resistome - or the reservoir of alleles within the genus, as well as its depth. Here, we use in vitro evolution of four commensal species to investigate the potential for and repeatability of resistance evolution to two antimicrobials, the macrolide azithromycin and the {beta}-lactam penicillin. After 20 days of selection, commensals evolved elevated minimum inhibitory concentrations (MICs) to penicillin and azithromycin in 11/16 and 12/16 cases respectively. Almost all cases of resistance emergence converged on mutations within ribosomal components or the mtrRCDE efflux pump for azithromycin-based selection, and mtrRCDE or penA for penicillin selection; thus, supporting constrained adaptive solutions despite divergent evolutionary starting points across the genus for these particular drugs. However, continuing to explore the paths to resistance across different experimental conditions and genomic backgrounds, which could shunt evolution down alternative evolutionary trajectories, will ultimately flesh out the full Neisseria resistome.

microbiology↗

bioRxiv2023

Epigenomic analysis of Formalin-Fixed Paraffin-Embedded samples by CUT&Tag

For more than a century, Formalin Fixed Paraffin Embedded (FFPE) sample preparation has been the preferred method for long-term preservation of biological material. However, the use of FFPE samples for epigenomic studies has been difficult because of chromatin damage from long exposure to high concentrations of formaldehyde. Previously, we introduced Cleavage Under Targeted Accessible Chromatin (CUTAC), an antibody-targeted chromatin accessibility mapping protocol based on CUT&Tag. Here we show that simple modifications of our single-tube CUTAC protocol are sufficient to produce high-resolution maps of paused RNA Polymerase II (RNAPII) at enhancers and promoters using FFPE samples. We find that transcriptional regulatory element differences produced by FFPE-CUTAC distinguish between mouse brain tumor specimens and identify regulatory element markers with high confidence and precision. Our simple work-flow is suitable for automation, making possible affordable epigenomic profiling of archived biological samples for biomarker identification, clinical applications and retrospective studies.

cancer biology↗

bioRxiv2023

An RNA seq-based reference landscape of human normal and neoplastic brain

In order to better understand the relationship between normal and neoplastic brain, we combined five publicly available large-scale datasets, correcting for batch effects and applying Uniform Manifold Approximation and Projection (UMAP) to RNA-seq data. We assembled a reference Brain-UMAP including 702 adult gliomas, 802 pediatric tumors and 1409 healthy normal brain samples, which can be utilized to investigate the wealth of information obtained from combining several publicly available datasets to study a single organ site. Normal brain regions and tumor types create distinct clusters and because the landscape is generated by RNA seq, comparative gene expression profiles and gene ontology patterns are readily evident. To our knowledge, this is the first meta-analysis that allows for comparison of gene expression and pathways of interest across adult gliomas, pediatric brain tumors, and normal brain regions. We provide access to this resource via the open source, interactive online tool Oncoscape, where the scientific community can readily visualize clinical metadata, gene expression patterns, gene fusions, mutations, and copy number patterns for individual genes and pathway over this reference landscape.

bioinformatics↗

bioRxiv2022

Expression of YAP1-MAML2 and constitutively active YAP1 drive the formation of meningioma-like tumors in mice that resemble NF2-mutant meningiomas

YAP1 is a transcriptional co-activator regulated by the Hippo Signaling Pathway, including NF2. Meningiomas are the most common primary brain tumors, a large percentage exhibit heterozygous loss of chromosome 22 (harboring the NF2 gene) and functional inactivation of the remaining NF2 copy, implicating oncogenic YAP activity in these tumors. Recently, fusions between YAP1 and MAML2 have been identified in a subset of pediatric NF2-wild type meningiomas. Here, we show that human YAP1-MAML2-positive meningiomas resemble NF2-mutant meningiomas by global and YAP-related gene expression signatures. We then show that expression of YAP1-MAML2 in mice induces tumors that resemble human YAP1 fusion-positive and NF2-mutant meningiomas by gene expression. We demonstrate that YAP1-MAML2 primarily functions by exerting TEAD-dependent YAP activity that is resistant to Hippo signaling. Treatment with YAP-TEAD inhibitors is sufficient to inhibit the viability of YAP1-MAML2-driven mouse tumors ex vivo. Finally, we show that expression of constitutively active YAP1 (S127/397A-YAP1) is sufficient to induce similar tumors suggesting that the YAP component of the gene fusion is the critical driver of these tumors. In summary, our results implicate YAP1-MAML2 as a causal oncogenic driver and highlight TEAD-dependent YAP activity as an oncogenic driver in YAP1-MAML2-fusion meningioma as well as NF2-mutant meningioma in general.

cancer biology↗

bioRxiv2022

Oncogenic role of a developmentally regulated NTRK2 splice variant

Temporally-regulated alternative splicing choices are vital for proper development yet the wrong splice choice may be detrimental. Here we highlight a novel role for the neurotrophin receptor splice variant TrkB.T1 in neurodevelopment, embryogenesis, transformation, and oncogenesis across multiple tumor types in both humans and mice. TrkB.T1 is the predominant NTRK2 isoform across embryonic organogenesis and forced over-expression of this embryonic pattern causes multiple solid and nonsolid tumors in mice in the context of tumor suppressor loss. TrkB.T1 also emerges the predominant NTRK isoform expressed in a wide range of adult and pediatric tumors, including those harboring TRK fusions. Affinity purification-mass spectrometry (AP-MS) proteomic analysis reveals TrkB.T1 has distinct interactors with known developmental and oncogenic signaling pathways such as Wnt, TGF-{beta}, Hedgehog, and Ras. From alterations in splicing factors to changes in gene expression, the discovery of isoform specific oncogenes with embryonic ancestry has the potential to shape the way we think about developmental systems and oncology.

cancer biology↗

bioRxiv2021

Single-cell RNA Sequencing Reveals Immunosuppressive Myeloid Cell Diversity and Restricted Cytotoxic Effector Cell Trafficking and Activation During Malignant Progression in Glioma

Low grade gliomas (LGG) account for about two-thirds of all glioma diagnoses in adolescents and young adults (AYA) and malignant progression of these patients leads to dismal outcomes. Recent studies have shown the importance of the dynamic tumor microenvironment in high-grade gliomas (HGG), yet its role is still poorly understood in low-grade glioma malignant progression. Here, we investigated the heterogeneity of the immune microenvironment using a platelet-derived growth factor (PDGF)-driven RCAS (replication-competent ASLV long terminal repeat with a splice acceptor) glioma model that recapitulates the malignant progression of low to high-grade glioma in humans and also provides a model system to characterize immune cell trafficking and evolution. To illuminate changes in the immune cell landscape during tumor progression, we performed single-cell RNA sequencing on immune cells isolated from animals bearing no tumor (NT), LGG and HGG, with a particular focus on the myeloid cell compartment, which is known to mediate glioma immunosuppression. LGGs demonstrated significantly increased infiltrating T cells, CD4 T cells, CD8 T cells, B cells, and natural killer cells in the tumor microenvironment, whereas HGGs significantly abrogated this infiltration. Our study identified two distinct macrophage clusters in the tumor microenvironment; one cluster appeared to be bone marrow-derived while another was defined by overexpression of Trem2, a marker of tumor associated macrophages. Our data demonstrates that these two distinct macrophage clusters show an immune-activated phenotype (Stat1, Tnf, Cxcl9 and Cxcl10) in LGG which evolves to an immunosuppressive state (Lgals3, Apoc1 and Id2) in HGG that restricts T cell recruitment and activation. We identified CD74 and macrophage migration inhibition factor (MIF) as potential targets for these distinct macrophage populations. Interestingly, these results were mirrored by our analysis of the TCGA dataset, which demonstrated a statistically significant association between CD74 overexpression and decreased overall survival in AYA patients with grade II gliomas. Targeting immunosuppressive myeloid cells and intra-tumoral macrophages within this therapeutic window may ameliorate mechanisms associated with immunosuppression before and during malignant progression.

cancer biology↗

bioRxiv2021

Machine Learning Identifies Ponatinib as a Potent Inhibitor of SARS-CoV2-induced Cytokine Storm

Although 15-20% of COVID-19 patients experience hyper-inflammation induced by massive cytokine production, cellular triggers of this process and strategies to target them remain poorly understood. Here, we show that the N-terminal domain (NTD) of the spike protein from the SARS-CoV-2 and emerging variants B1.1.7 and B.1.351 substantially induces multiple inflammatory molecules in human monocytes and PBMCs. Further, we identified several protein kinases, including JAK1, EPHA7, IRAK1, MAPK12, and MAP3K8, as essential downstream mediators of NTD-induced cytokine release. Additionally, we found that the FDA-approved, multi-kinase inhibitor Ponatinib is a potent inhibitor of the NTD-mediated cytokine storm. Taken together, we propose that agents targeting multiple kinases required for the SARS-CoV-2-mediated cytokine storm, such as Ponatinib, may represent an attractive therapeutic option for treating moderate to severe COVID-19.

systems biology↗