A5077007849- Cancer, Hypoxia, and Metabolism
- Melanoma and MAPK Pathways
- Gene Regulatory Network Analysis
- Advanced Breast Cancer Therapies
- Cancer Genomics and Diagnostics
- SARS-CoV-2 and COVID-19 Research
- RNA modifications and cancer
- Mitochondrial Function and Pathology
- Epigenetics and DNA Methylation
- Endoplasmic Reticulum Stress and Disease
- Cannabis and Cannabinoid Research
- Computational Drug Discovery Methods
- Cholinesterase and Neurodegenerative Diseases
- Healthcare cost, quality, practices
- Nitric Oxide and Endothelin Effects
- Protein Kinase Regulation and GTPase Signaling
- PARP inhibition in cancer therapy
- COVID-19 and healthcare impacts
- Histone Deacetylase Inhibitors Research
- FOXO transcription factor regulation
- RNA regulation and disease
- Prostate Cancer Treatment and Research
- Brain Metastases and Treatment
- COVID-19 Clinical Research Studies
- Microtubule and mitosis dynamics
University of Chicago
2020-2025
University College London
2021
University College London Hospitals NHS Foundation Trust
2021
The spread of SARS-CoV-2 and ongoing COVID-19 pandemic underscores the need for new treatments. Here we report that cannabidiol (CBD) inhibits infection in cells mice. CBD its metabolite 7-OH-CBD, but not THC or other congeneric cannabinoids tested, potently block replication lung epithelial cells. acts after viral entry, inhibiting gene expression reversing many effects on host transcription. part by up-regulating IRE1α RNase endoplasmic reticulum (ER) stress response interferon signaling...
ABSTRACT The rapid spread of COVID-19 underscores the need for new treatments. Here we report that cannabidiol (CBD), a compound produced by cannabis plant, inhibits SARS-CoV-2 infection. CBD and its metabolite, 7-OH-CBD, but not congeneric cannabinoids, potently block replication in lung epithelial cells. acts after cellular infection, inhibiting viral gene expression reversing many effects on host transcription. induces interferon up-regulates antiviral signaling pathway. A cohort human...
SARS-CoV-2 is the third lethal respiratory coronavirus, after MERS-CoV and SARS-CoV, to emerge this century, causing millions of deaths worldwide. Other common coronaviruses such as HCoV-OC43 cause less severe disease.
Abstract Hypoxia, a hallmark of aggressive solid tumors, promotes metastasis and therapy resistance by activating factors such as hypoxia-inducible (HIFs) that support cellular adaptation tumorigenesis. Under hypoxic stress, transcription like HIFs X-box-binding protein 1 (XBP1) are activated bind to unfolded response element (UPRE) hypoxia (HRE) motifs, regulating oncogenic gene expression. We identified the core HRE motif (5’-ACGTG-3’) is embedded within canonical UPRE (5’-TGACGTGG-3’),...
Metastasis suppression by high-dose, multi-drug targeting is unsuccessful due to network heterogeneity and compensatory activation. Here, we show that driver signaling capacity limited inhibition of core pathways a more effective anti-metastatic strategy. This principle underlies the action physiological metastasis suppressor, Raf Kinase Inhibitory Protein (RKIP), moderately decreases stress-regulated MAP kinase activity, reducing output transcription factors such as pro-metastastic BACH1...
SUMMARY Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed over 6 million individuals worldwide and continues to spread in countries where vaccines are not yet widely available, or its citizens hesitant become vaccinated. Therefore, it is critical unravel the molecular mechanisms that allow SARS-CoV-2 other coronaviruses infect overtake host machinery of human cells. Coronavirus replication triggers endoplasmic reticulum (ER) stress activation unfolded protein response...
Abstract Hypoxia, low oxygen availability at the tissue level, is a key driver of metastasis in solid tumors. Oxygen-sensitive activation hypoxia-induced transcription factors part regulated by prolyl hydroxylase domain proteins (PHDs). We and others previously showed that BTB CNC homolog 1 (BACH1) factor promotes various cancer types. In accompanying work, we show BACH1 prolyl-hydroxylated degraded an oxygen-dependent manner triple-negative breast (TNBC). Here lacking its hydroxylated...
Abstract Hypoxia is an important hallmark of aggressive solid tumors and a key driver metastasis resistance to therapy. Hypoxic stress induces the activation various factors, such as hypoxia-inducible factors (HIFs), which facilitate cellular adaptation promote tumorigenesis. Given complexity this mechanism, identifying novel targets that sensitize hypoxic therapy could have significant clinical impact. Here we show pro-metastatic BTB CNC homology 1 (BACH1) transcription factor...
Abstract Hypoxia is an important hallmark of aggressive solid tumors and a key driver metastasis resistance to therapy. Hypoxic stress induces the activation various factors, such as hypoxia- inducible factors (HIFs), which facilitate cellular adaptation promote tumorigenesis. Given complexity this mechanism, identifying novel targets that sensitize hypoxic therapy could have significant clinical impact. We demonstrate HIF-independent induction BACH1 within multiple TNBC (Triple-Negative...
ABSTRACT Metastasis suppression by high-dose, multi-drug targeting is largely unsuccessful due to network heterogeneity and compensatory activation. Here we show that driver signaling capacity limited inhibition of its core pathways a more effective anti-metastatic strategy. This principle underlies the action physiological metastasis suppressor, Raf Kinase Inhibitory Protein, which moderately decreases stress-regulated MAP kinase activity, reducing output metastatic transcription factor...
Abstract Hypoxia is an important hallmark of aggressive solid tumors. Here we show that the pro-metastatic BTB and CNC homology 1 (BACH1) transcription factor prolyl-hydroxylated by HIF Prolyl Hydroxylase (PHD1) in oxygen-dependent manner. Using mass spectrometry, identified two major prolyl hydroxylation sites BACH1 demonstrate increased protein turnover normoxia. Notably, a clinically relevant mutant (BACH1M) resistant to displays enhanced DNA binding capacity. Triple-negative breast...
Abstract Tumor cell heterogeneity has been implicated in metastatic progression of solid tumors such as triple-negative breast cancer (TNBC), leading to resistance and recurrence. We hypothesize that genes with low cell-to-cell transcriptional variability are more effective therapeutic targets, use a metric will identify new regulators. Using single RNA sequencing, we demonstrate the metastasis suppressor Raf Kinase Inhibitory Protein (RKIP/PEBP1) reduced overall TNBC xenograft including...
Abstract Triple-negative breast cancer (TNBC), the most aggressive subtype of cancer, is more prevalent among African American and underserved female populations. Hypoxia has recently been identified as one main drivers TNBC, particularly within cohort. Therefore, it important to identify target key regulators hypoxia. Here we show that pro-metastatic transcription factor BACH1 induced by hypoxia regulates response in TNBC tumor cells. protein destabilized via an oxygen-dependent...
Abstract High-dose, single-drug treatment is unsuccessful at suppressing metastasis due to cellular heterogeneity and feedback activation. Here we demonstrate that targeting driver network signaling capacity by limited inhibition multiple nodes a more effective anti-metastatic strategy. A physiological suppressor, Raf Kinase Inhibitory Protein, decreases the activity of kinases in stress-regulated MAP kinase (MAPK) reduces output metastatic transcription factor BACH1 upregulates...
Abstract Tumor cell heterogeneity has been strongly implicated in metastatic progression of solid tumors such as breast cancer, leading to resistance and recurrence. We hypothesize that inhibiting metastasis will reduce tumor thereby increase therapeutic sensitivity. To test this hypothesis, we expressed the suppressor Raf Kinase Inhibitory Protein (RKIP or PEBP1) triple-negative cancer (TNBC) cells a means comparing variation gene expression between individual versus non-metastatic tumors....
Abstract Tumor cell heterogeneity has been strongly implicated in metastatic progression of solid tumors such as breast cancer, leading to resistance and recurrence. We hypothesize that inhibiting metastasis will reduce tumor thereby increase therapeutic sensitivity. To test this hypothesis, we expressed the suppressor Raf Kinase Inhibitory Protein (RKIP or PEBP1) triple-negative cancer (TNBC) cells a means comparing variation gene expression between individual versus non-metastatic tumors....
Abstract Tumor cell heterogeneity has been strongly implicated in metastatic progression of solid tumors such as triple-negative breast cancer (TNBC), leading to resistance and recurrence. Raf Kinase Inhibitory Protein (RKIP or PEBP1) effectively suppresses metastasis TNBC but is lost many patients. We hypothesize that RKIP works part by reducing the variability gene expression cells. To test whether reduces overall transcriptional heterogeneity, we compared variation between individual...
Abstract Triple-negative breast cancer (TNBC) is an aggressive solid tumor characterized by a hypoxic phenotype that promotes metastatic progression and resistance to therapy. The canonical cellular response hypoxia largely driven inducible factors (HIFs) stimulate transcription of genes related angiogenesis, stem cells, cell survival, glucose iron metabolism. There growing evidence several factors, in addition HIFs, contribute the response. Thus, identifying novel mechanisms regulate this...
Abstract Tumor cell heterogeneity has been implicated in metastatic progression of solid tumors such as triple-negative breast cancer (TNBC), leading to resistance and recurrence. We hypothesized that genes with low cell-to-cell transcriptional variability may be effective therapeutic targets, analysis facilitate identification new regulators. Here we demonstrate, using single RNA sequencing, the metastasis suppressor Raf Kinase Inhibitory Protein (RKIP) reduced overall TNBC xenograft...