A5000962444- Protein Kinase Regulation and GTPase Signaling
- Advanced Proteomics Techniques and Applications
- Cytokine Signaling Pathways and Interactions
- Lung Cancer Treatments and Mutations
- Bioinformatics and Genomic Networks
- RNA modifications and cancer
- Peptidase Inhibition and Analysis
- Computational Drug Discovery Methods
- Machine Learning in Bioinformatics
- Ferroptosis and cancer prognosis
- Immunotherapy and Immune Responses
- TGF-β signaling in diseases
- Melanoma and MAPK Pathways
- Protein Tyrosine Phosphatases
- Receptor Mechanisms and Signaling
- Ubiquitin and proteasome pathways
- Autophagy in Disease and Therapy
- Cell Image Analysis Techniques
- Brain Metastases and Treatment
- Cancer, Hypoxia, and Metabolism
- Histone Deacetylase Inhibitors Research
- Endoplasmic Reticulum Stress and Disease
- Protein Degradation and Inhibitors
- Fibroblast Growth Factor Research
- Hippo pathway signaling and YAP/TAZ
Moffitt Cancer Center
2015-2025
Molecular Oncology (United States)
2013-2020
University of South Florida
2008-2011
How genomic and transcriptomic alterations affect the functional proteome in lung cancer is not fully understood. Here, we integrate DNA copy number, somatic mutations, RNA-sequencing, expression proteomics a cohort of 108 squamous cell (SCC) patients. We identify three proteomic subtypes, two which (Inflamed, Redox) comprise 87% tumors. The Inflamed subtype enriched with neutrophils, B-cells, monocytes expresses more PD-1. Redox tumours are for oxidation-reduction glutathione pathways...
Abstract Purpose: Covalent inhibitors of KRASG12C specifically target tumors driven by this form mutant KRAS, yet early studies show that bypass signaling drives adaptive resistance. Although several combination strategies have been shown to improve efficacy (KRASi), underlying mechanisms and predictive for patient enrichment are less clear. Experimental Design: We performed mass spectrometry–based phosphoproteomics analysis in cell lines after short-term treatment with ARS-1620. To...
Abstract Immunotherapy efficacy is limited in melanoma, and combinations of immunotherapies with other modalities have yielded improvements but also adverse events requiring cessation treatment. In addition to ineffective patient stratification, impaired by paucity intratumoral immune cells (itICs); thus, effective strategies safely increase itICs are needed. We report that dietary administration l -fucose induces fucosylation cell surface enrichment the major histocompatibility complex...
Abstract Melanoma incidence and mortality rates are historically higher for men than women. Although emerging studies have highlighted tumorigenic roles the male sex hormone androgen its receptor (AR) in melanoma, cellular molecular mechanisms underlying these sex-associated discrepancies poorly defined. Here, we delineate a previously undisclosed mechanism by which androgen-activated AR transcriptionally upregulates fucosyltransferase 4 ( FUT4 ) expression, drives melanoma invasiveness...
Abstract BRAF plays an indispensable role in activating the MEK/ERK pathway to drive tumorigenesis. Receptor tyrosine kinase and RAS-mediated activation have been extensively characterized, however, it remains undefined how function is fine-tuned by stimuli other than growth factors. Here, we report that response proinflammatory cytokines, subjected lysine 27-linked poly-ubiquitination melanoma cells ITCH ubiquitin E3 ligase. Lysine ubiquitination of recruits PP2A antagonize S365...
Highlights•Fascin is required for metabolic stress resistance in metastatic lung cancer•Fascin promotes mitochondrial OXPHOS through remodeling mtF-actin•Fascin augments the biogenesis of Complex I mtDNA homeostasis•The role fascin it to promote brain metastasisSummaryThe deregulation actin cytoskeleton has been extensively studied dissemination. However, post-dissemination dysregulation poorly understood. Here, we report that fascin, an actin-bundling protein, cancer colonization by...
Downstream signaling of physiological and pathological cell responses depends on post-translational modification such as ubiquitination. The mechanisms regulating downstream DNA damage response (DDR) are not completely elucidated. Sirtuin 1 (SIRT1), the founding member Class III histone deacetylases, regulates multiple steps in DDR is closely associated with many processes. However, role or ubiquitination SIRT1 during unclear. We show that dynamically distinctly ubiquitinated to damage. was...
Leptomeningeal disease (LMD) occurs when malignant cells seed into the leptomeningeal space and cerebrospinal fluid (CSF), leading to severe neurological symptoms very short survivals. LMD in 5to15% of cancer patients is most common breast, melanoma, lung, lymphomas. tumors are generally resistant all standard care therapies. To better understand biology we used comprehensive multiomic analyses CSF specimens from with different primary its immune metabolic tumor microenvironment. Single cell...
The Zika virus (ZIKV) is a mosquito-borne Flavivirus and can be transmitted through an infected mosquito bite or human-to-human interaction by sexual activity, blood transfusion, breastfeeding, perinatal exposure. After the 2015–2016 outbreak in Brazil, strong link between ZIKV infection microcephaly emerged. specifically targets human neural progenitor cells, suggesting that proteins encoded bind inactivate host cell proteins, leading to microcephaly. Here, we present systematic annotation...
The NAD(+)-dependent deacetylase SirT1 regulates gene silencing and genomic stability in response to nutrient deprivation DNA damage. An important regulator of mammalian cells is DBC1 (deleted breast cancer 1; KIAA1967 or CCAR2), which binds inhibits the deacetylation substrates. Recent studies have revealed that ATM/ATR-mediated phosphorylation promotes binding SirT1. Here we show modified by acetylation on two N-terminal lysine residues (K112 K215). MYST family histone acetyltransferase...
Lung cancer is associated with high prevalence and mortality, despite significant successes targeted drugs in genomically defined subsets of lung immunotherapy, the majority patients currently does not benefit from these therapies. Through a drug screen, we found recently approved multi-kinase inhibitor midostaurin to have potent activity several cells independent its intended target, PKC, or specific genomic marker. To determine underlying mechanism action applied layered functional...
Abstract Analysis of tyrosine kinase signaling is critical for the development targeted cancer therapy. Currently, immunoprecipitation phosphotyrosine (pY) peptides prior to liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) used profile substrates. A typical protocol requests 10 mg total protein from ≈10 8 cells or 50–100 tissue. Large sample requirements can be cost prohibitive not feasible certain experiments. Sample multiplexing using chemical labeling reduces amount required each...
The clinical utility of histone/protein deacetylase (HDAC) inhibitors in combinatorial regimens with proteasome for patients relapsed and refractory multiple myeloma (MM) is often limited by excessive toxicity due to HDAC inhibitor promiscuity HDACs. Therefore, more selective inhibition minimizing off-target may increase the effectiveness inhibitors. We demonstrated that plasma cell development survival are dependent upon HDAC11, suggesting this enzyme a promising therapeutic target MM. Mice...
Abstract Peptide-based proteomics supports identification and quantification as well localization of post-translational modifications (PTMs) within proteins extracted from biological samples. The ‘bottom-up’ approach involves the digestion into peptide fragments that can be detected sequenced with liquid chromatography coupled tandem mass spectrometry (LC-MS/MS). A web-based application, iPEP, was developed to compare effectiveness different proteolytic digests in detecting specific...
Prediction of lung cancer metastasis relies on post-resection assessment tumor histology, which is a severe limitation since only minority patients are diagnosed with resectable disease. Therefore, characterization metastasis-predicting biomarkers in pre-resection small biopsy specimens urgently needed. Here we report biomarker consisting the phosphorylation retinoblastoma protein (Rb) serine 249 combined elevated p39 expression. This correlates epithelial-to-mesenchymal transition traits...
Brain metastasis cancer-associated fibroblasts (bmCAFs) are emerging as crucial players in the development of breast cancer brain (BCBM), but our understanding underlying molecular mechanisms is limited. In this study, we aim to elucidate pathological contributions fucosylation (the post-translational modification proteins by dietary sugar L-fucose) tumor-stromal interactions that drive BCBM. Here, report patient-derived bmCAFs secrete high levels polio virus receptor (PVR), which enhance...
Abstract Head and neck squamous cell carcinoma (HNSCC) presents a challenging clinical scenario due to its recurrence propensity despite existing treatments. Altered intrinsic signaling pathways significantly contribute therapeutic resistance, demanding exploration of novel strategies induce tumor demise. Dysregulated cycle DNA damage repair constitute pivotal events driving HNSCC progression, offering potential targets.CHK1 CHK2, regulators the replication checkpoint, are promising targets...
Abstract Leptomeningeal disease (LMD) occurs when tumors seed into the leptomeningeal space and cerebrospinal fluid (CSF), leading to severe neurological deterioration poor survival outcomes. We utilized comprehensive multi-omic analyses of CSF from patients with melanoma, breast cancer lymphoma LMD demonstrate an immunosuppressive cellular microenvironment dominated by inactive, dysfunctional T cells alternatively activated macrophages. These findings were confirmed in mouse models LMD....