A5005440027- interferon and immune responses
- Lung Cancer Research Studies
- Cytokine Signaling Pathways and Interactions
- RNA modifications and cancer
- MicroRNA in disease regulation
- Monoclonal and Polyclonal Antibodies Research
- Immunotherapy and Immune Responses
- Cancer Immunotherapy and Biomarkers
- Neuroblastoma Research and Treatments
- Cancer-related molecular mechanisms research
- Ubiquitin and proteasome pathways
- Cancer Mechanisms and Therapy
- Bacteriophages and microbial interactions
- Immune Cell Function and Interaction
- Peptidase Inhibition and Analysis
- Immune cells in cancer
- NF-κB Signaling Pathways
- Fungal Infections and Studies
- CAR-T cell therapy research
- Cancer, Hypoxia, and Metabolism
- Cancer Research and Treatments
- Advanced Biosensing Techniques and Applications
- Proteoglycans and glycosaminoglycans research
- Brain Metastases and Treatment
- Circular RNAs in diseases
Merck & Co., Inc., Rahway, NJ, USA (United States)
2025
Dana-Farber Cancer Institute
2017-2024
Harvard University
2019-2023
Massachusetts General Hospital
2020
Brigham and Women's Hospital
2017-2019
Dana-Farber Brigham Cancer Center
2019
National Student Clearinghouse Research Center
2014
Duke University
2013-2014
Duke University Hospital
2012-2014
Duke Medical Center
2012-2014
Abstract Small cell lung carcinoma (SCLC) is highly mutated, yet durable response to immune checkpoint blockade (ICB) rare. SCLC also exhibits cellular plasticity, which could influence its immunobiology. Here we discover that a distinct subset of uniquely upregulates MHC I, enriching for ICB benefit. In vitro modeling confirms epigenetic recovery I in following loss neuroendocrine differentiation, tracks with derepression STING. Transient EZH2 inhibition expands these nonneuroendocrine...
Immunotherapy has had a tremendous impact on cancer treatment in the past decade, with hitherto unseen responses at advanced and metastatic stages of disease. However, aggressive brain tumor glioblastoma (GBM) is highly immunosuppressive remains largely refractory to current immunotherapeutic approaches. The stimulator interferon genes (STING) DNA sensing pathway emerged as next-generation immunotherapy target potent local immune stimulatory properties. Here, we investigated status STING GBM...
Activation of the stimulator interferon genes (STING) pathway promotes antitumor immunity but STING agonists have yet to achieve clinical success. Increased understanding mechanism action in human tumors is key developing therapeutic combinations that activate effective innate immunity. Here, we report malignant pleural mesothelioma cells robustly express and are responsive agonist treatment ex vivo. Using dynamic single-cell RNA sequencing explants treated with a agonist, observed CXCR3...
Abstract Therapeutic blockade of PD-1:PD-L1/L2 interactions is effective in many cancers, particularly those with pre-existing inflammation and T cell infiltration. We identified a correlation between high interleukin 4 induced 1 (IL4I1) gene expression within the tumor micorenvironment (TME) tumors response to PD-1 inhibitor pembrolizumab (pembro). IL4I1 protein secreted by myeloid cells into extracellular TME where it generates hydrogen peroxide upon deamination amino acid substrates,...
Abstract Triple-negative breast cancer (TNBC) is a heterogeneous disease enriched for mutations in PTEN and dysregulation of innate immune signaling. Here, we demonstrate that Rab7, recently identified substrate phosphatase activity, also the signaling kinases TANK-binding kinase 1 (TBK1)/IκB ϵ (IKKϵ) on same serine-72 (S72) site. An unbiased search novel TBK1/IKKϵ substrates using stable isotope labeling with amino acids cell culture phosphoproteomic analysis Rab7-S72 as top hit. PTEN-null...
Intratumoral recruitment of immune cells following innate activation is critical for anti-tumor immunity and involves cytosolic dsDNA sensing by the cGAS/STING pathway. We have previously shown that KRAS-LKB1 (KL) mutant lung cancer, which resistant to PD-1 blockade, exhibits silencing STING, impaired tumor cell production chemoattractants, T exclusion. Since vasculature also a gatekeeper infiltration into tumors, we developed novel microfluidic model study KL tumor-vascular interactions....
Abstract Immunotherapy has shown limited efficacy in patients with EGFR-mutated lung cancer. Efforts to enhance the immunogenicity of cancer have been unsuccessful date. Here, we discover that MET amplification, most common mechanism resistance third-generation EGFR tyrosine kinase inhibitors (TKI), activates tumor cell STING, an emerging determinant (1). However, STING activation was restrained by ectonucleosidase CD73, which is induced MET-amplified, EGFR-TKI–resistant cells. Systematic...
Abstract Small-cell lung cancer (SCLC) is the most lethal type of cancer. Paradoxically, this tumor displays an initial exquisite response to chemotherapy; however, at relapse, highly resistant subsequent available therapies. Here, we report that expression three prime repair exonuclease 1 (TREX1) strongly induced in chemoresistant SCLCs. Assay for transposase-accessible chromatin using sequencing and immunoprecipitation revealed a significant increase accessibility transcriptional activity...
Abstract Neuroendocrine to nonneuroendocrine plasticity supports small cell lung cancer (SCLC) tumorigenesis and promotes immunogenicity. Approximately 20% 25% of SCLCs harbor loss-of-function (LOF) NOTCH mutations. Previous studies demonstrated that functions as a SCLC tumor suppressor, but can also drive support growth. Given the dual functionality NOTCH, it is not understood why select for LOF mutations how these affect tumorigenesis. In CRISPR-based genetically engineered mouse model...
Growth factors and their receptors coordinate neuronal differentiation during development, yet roles in the pediatric tumor neuroblastoma remain unclear. Comparison of mRNA from benign neuroblastic tumors neuroblastomas revealed that expression type III TGF-β receptor (TGFBR3) decreases with advancing stage this loss correlates a poorer prognosis. Patients MYCN oncogene amplification low TGFBR3 were more likely to have an adverse outcome. In vitro, TβRIII was epigenetically suppressed by...
Neuroblastoma prognosis is dependent on both the differentiation state and stromal content of tumor. tumor stroma thought to suppress neuroblast growth via release soluble differentiating factors. Here, we identified critical growth-limiting components secretome designed a potential therapeutic strategy based their central mechanism action. We demonstrated that expression heparan sulfate proteoglycans (HSPGs), including TβRIII, GPC1, GPC3, SDC3, SDC4, low in neuroblasts high Schwannian...
Brain metastases are the most common brain tumors in adults, whose management remains nuanced. Improved understanding of risk factors for surgical complications and mortality may guide treatment decisions.A nationwide, multicenter analysis was conducted with a retrospective cohort. Adult patients 2012-2015 American College Surgeons National Surgical Quality Improvement Project (ACS NSQIP) databases who received craniotomy resection metastasis were included.3500 cases analyzed, which 17%...
<p>Figure S4 shows TREX1 depletion increases sensitivity of resistant SCLC cells to chemotherapy</p>
<p>Figure S5 shows TREX1 expression is induced in post-treated SCLC PDX</p>
<p>Drug transporter expression levels in H69AR <i>vs</i> H69</p>
<p>qPCR primer sequences</p>
<p>Figure S3 shows immunogenicity is induced in TREX1 depleted cells</p>
<p>Figure S2 shows TREX1 loss suppresses SCLC growth and induces immune response</p>
<p>Figure S1 shows TREX1 expression is induced in drug resistant SCLC cells</p>
<p>Treatment history of PDX tumors</p>