A5081078513- Cancer Mechanisms and Therapy
- Pancreatic and Hepatic Oncology Research
- RNA modifications and cancer
- Cancer Cells and Metastasis
- Peptidase Inhibition and Analysis
- PI3K/AKT/mTOR signaling in cancer
- Medical Imaging and Pathology Studies
- Chronic Lymphocytic Leukemia Research
- Protein Degradation and Inhibitors
- Chemical Reactions and Isotopes
- Lung Cancer Treatments and Mutations
- Cancer-related molecular mechanisms research
- MicroRNA in disease regulation
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Fibroblast Growth Factor Research
- Neonatal Respiratory Health Research
- Brain Metastases and Treatment
- Computational Drug Discovery Methods
- Endoplasmic Reticulum Stress and Disease
- Microtubule and mitosis dynamics
- Growth Hormone and Insulin-like Growth Factors
- Virus-based gene therapy research
- Hippo pathway signaling and YAP/TAZ
- Multiple Myeloma Research and Treatments
- Cancer Treatment and Pharmacology
Duke University
2018-2023
Duke Medical Center
2019-2023
Brigham Young University
2013-2014
Brain metastases are a common consequence of advanced lung cancer, resulting in cranial neuropathies and increased mortality. Currently, there no effective therapies to treat brain due lack actionable targets failure systemic penetrate the blood-brain barrier (BBB). Here we identify an autocrine signaling axis required for adenocarcinoma metastasis, whereby nuclear accumulation TAZ transcriptional co-activator drives expression panel transcripts enriched metastases, including ABL2 AXL,...
Abstract During apoptosis, mitochondrial outer membrane permeabilization (MOMP) enables certain matrix macromolecules to escape into the cytosol. However, fate of RNA (mtRNA) during apoptosis is unknown. Here, we demonstrate that MOMP results in cytoplasmic release mtRNA and executioner caspases-3 -7 (casp3/7) prevent from triggering inflammatory signaling. In setting genetic or pharmacological casp3/7 inhibition, apoptotic insults result activation MDA5/MAVS/IRF3 pathway drive Type I...
Significance Among all cancer types, lung patients exhibit the highest prevalence of brain metastasis, often associated with cognitive impairment, seizures, decline in quality life, and decreased survival. Limited therapeutic options are currently available to treat metastasis. A comprehensive understanding signaling pathways transcriptional networks required for survival growth brain-metastatic cells is needed develop effective strategies this disease. Here, we report that Heat Shock...
Mesenchymal stem cells (MSCs) are recruited and activated by solid tumors play a role in tumor progression metastasis. Here we show that MSCs promote metastasis panel of non-small cell lung cancer (NSCLC) cells. elicit transcriptional alterations leading to increased expression factors implicated the epithelial-to-mesenchymal transition (EMT) secreted proteins including matrix metalloproteinase-9 (MMP9). enhance secretion enzymatically active MMP9 adenocarcinoma High is linked low survival...
Abstract Background Medulloblastoma is the most common malignant pediatric brain tumor, and leptomeningeal dissemination (LMD) of medulloblastoma both portends a poorer prognosis at diagnosis incurable recurrence. The biological mechanisms underlying LMD are unclear. Abelson (ABL) tyrosine kinase family members, ABL1 ABL2, have been implicated in cancer cell migration, invasion, adhesion, metastasis, chemotherapy resistance, upstream mediators oncogene c-MYC fibroblasts lung cells. However,...
PIK3CA is the second most mutated gene in cancer leading to aberrant PI3K/AKT/mTOR signaling and increased translation, proliferation, survival. Some 4%-25% of gastric cancers display activating mutations, including 80% Epstein-Barr virus-associated GCs. Small molecules, pan-PI3K dual PI3K/mTOR inhibitors, have shown moderate success clinically, due broad on-target/off-tissue effects. Thus, isoform-specific mutant selective inhibitors been significant interest. However, drug resistance a...
The hypoxia-inducible factor 1-α (HIF-1α) enables cells to adapt and respond hypoxia (Hx), the activity of this transcription is regulated by several oncogenic signals cellular stressors. While pathways controlling normoxic degradation HIF-1α are well understood, mechanisms supporting sustained stabilization under Hx less clear. We report that ABL kinase protects from proteasomal during Hx. Using a fluorescence-activated cell sorting (FACS)-based CRISPR/Cas9 screen, we identified as...
Targeting mitochondrial metabolism has emerged as a treatment option for cancer patients. The ABL tyrosine kinases promote metastasis, and enhanced signaling is associated with poor prognosis in lung adenocarcinoma Here we show that kinase allosteric inhibitors impair integrity decrease oxidative phosphorylation. To identify metabolic vulnerabilities enhance this phenotype, utilized CRISPR/Cas9 loss-of-function screen identified HMG-CoA reductase, the rate-limiting enzyme of mevalonate...
<p>Figure S7 shows loss of PIM1 re-sensitizes resistant cells to BYL719</p>
<p>Figure S6 shows down-regulation of RUNX1 in BYL719 resistant cells</p>
<p>Sequences of guide RNAs used to generate genetic knockouts</p>
<p>Figure S4 shows loss of BCL-XL and BYL719 treatment in additional gastric cancer cell line</p>
<p>Z-transformed difference scores for each cell line as calculated from beta scores</p>
<p>Antibody dilutions for primary and secondary antibodies used</p>
<p>Figure S5 shows BH3 mimetics and MCL1 modifiers in combination with BYL719</p>
<p>Beta scores generated for DMSO and BYL719 treated populations using MAGeCK analysis pipeline</p>
<p>Genes included in the CRISPR screening library</p>
<p>Quantification of Human Phospho-Proteome Array</p>
<p>Genes present in each of the 8 clusters</p>
<p>QPCR primers</p>