A5012568511- Lung Cancer Treatments and Mutations
- Cancer, Hypoxia, and Metabolism
- PI3K/AKT/mTOR signaling in cancer
- Lung Cancer Research Studies
- Cancer Immunotherapy and Biomarkers
- Mast cells and histamine
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Immune cells in cancer
- Cancer, Lipids, and Metabolism
- Cancer-related molecular mechanisms research
- Immunotherapy and Immune Responses
- Immune Cell Function and Interaction
- RNA modifications and cancer
- CAR-T cell therapy research
- Chromatin Remodeling and Cancer
- Ferroptosis and cancer prognosis
- Synthesis and Biological Evaluation
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Circular RNAs in diseases
- Neuroblastoma Research and Treatments
- Cancer Genomics and Diagnostics
- Cancer Mechanisms and Therapy
- Genomics, phytochemicals, and oxidative stress
- Toxin Mechanisms and Immunotoxins
- Cell Image Analysis Techniques
Yale University
2018-2024
University of New Haven
2021-2022
Dana-Farber Cancer Institute
2022
Broad Institute
2022
University of Pennsylvania
2012-2019
Cancer Research Institute
2012-2015
Acquired resistance to tyrosine kinase inhibitors (TKI), such as osimertinib used treat EGFR-mutant lung adenocarcinomas, limits long-term efficacy and is frequently caused by non-genetic mechanisms. Here, we define the chromatin accessibility gene regulatory signatures of sensitive resistant cell patient-derived models uncover a role for mammalian SWI/SNF remodeling complexes in TKI resistance. By profiling mSWI/SNF genome-wide localization, identify both shared cancer line-specific targets...
Abstract The limited efficacy of currently approved immunotherapies in EGFR-driven lung adenocarcinoma (LUAD) underscores the need to better understand alternative mechanisms governing local immunosuppression fuel novel therapies. Elevated surfactant and GM-CSF secretion from transformed epithelium induces tumor-associated alveolar macrophage (TA-AM) proliferation, which supports tumor growth by rewiring inflammatory functions lipid metabolism. TA-AM properties are driven increased...
Immunotherapy resistance in non-small cell lung cancer (NSCLC) may be mediated by an immunosuppressive microenvironment, which can shaped the mutational landscape of tumor. Here, we observed genetic alterations PTEN/PI3K/AKT/mTOR pathway and/or loss PTEN expression >25% patients with NSCLC, higher frequency squamous carcinomas (LUSC). Patients PTEN-low tumors had levels PD-L1 and PD-L2 showed worse progression-free survival when treated immunotherapy. Development a Pten-null LUSC mouse model...
Expression of the long noncoding RNA (lncRNA) metastasis–associated lung adenocarcinoma transcript 1 ( MALAT1 ) correlates with tumor progression and metastasis in many types. However, impact mechanism action by which promotes metastatic disease remain elusive. Here, we used CRISPR activation (CRISPRa) to overexpress MALAT1/Malat1 patient-derived (LUAD) cell lines autochthonous K-ras/p53 LUAD mouse model. Malat1 overexpression was sufficient promote mice. Overexpression enhanced mobility...
Abstract Synthetic biological tools that enable precise regulation of gene function within in vivo systems have enormous potential to discern diverse physiological settings. Here we report the development and characterization a synthetic switch that, when targeted mouse germline, enables conditional inactivation, reports expression allows inducible restoration gene. Gene inactivation reporter is achieved through Cre-mediated stable inversion an integrated gene-trap reporter, whereas afforded...
Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) like erlotinib are effective for treating patients with EGFR mutant lung cancer; however, drug resistance inevitably emerges. Approaches to combine immunotherapies and targeted therapies overcome or delay have been hindered by limited knowledge of the effect on tumor-infiltrating immune cells.Using mouse models, we studied immunological profile EGFR-driven tumors before after treatment.We found that triggered...
Abstract Senescence is an important p53-controlled tumor suppressor program that not only opposes the proliferation of cancer cells but also promotes their immune-mediated clearance in certain contexts. In hepatocellular cancer, p53 induction innate immune cell-mediated senescent wherein natural killer (NK) seem to play primary sentinel role. Whether NK surveil other types when activated promote a senescence response unknown. To identify role and cell have on surveillance destruction lung...
Despite the established use of immune checkpoint inhibitors (ICIs) to treat non-small cell lung cancer (NSCLC), only a subset patients benefit from treatment and ∼50% whose tumors respond eventually develop acquired resistance (AR). To identify novel drivers AR, we generated murine Msh2 knock-out (KO) that initially responded but developed AR anti-PD-1, alone or in combination with anti-CTLA-4. Resistant harbored decreased infiltrating T cells reduced cell-intrinsic MHC-I MHC-II levels, yet...
Abstract Metastasis is the main cause of cancer deaths but molecular events leading to metastatic dissemination remain incompletely understood. Despite reports linking aberrant expression long noncoding RNAs (lncRNAs) with increased incidence , in vivo evidence establishing driver roles for lncRNAs progression lacking. Here, we report that overexpression metastasis-associated lncRNA Malat1 (metastasis-associated lung adenocarcinoma transcript 1) autochthonous K-ras/p53 mouse model (LUAD)...
Abstract Immune checkpoint inhibitors (ICIs) targeting PD-L1/PD-1 have dramatically improved the management of NSCLC patients. Nevertheless, more than 50% patients will present primary resistance or develop secondary within 12-25 months after treatment initiation. The mechanisms to ICIs may depend on tumor-intrinsic molecular/genetic alterations that generate an immunosuppressive tumor microenvironment (isTME). Using In silico analyses (TCGA and AACR-GENIE cohorts), protein expression...
<p>Figure S6: Single cell analysis of tumorigenesis in humans reveals rewired LUAD patient macrophage lipid and mitochondrial metabolism.</p>
<p>Figure S8: AMs transfer nutrients to tumor cells.</p>
<p>Figure S8: AMs transfer nutrients to tumor cells.</p>
<p>Figure S9: Statins inhibit EGFRmutant tumor cell growth and oncogenic signaling.</p>
<p>Table S1: BALF Patient Sample Clinical Features</p>
<p>Figure S4: Deficiency of PPARγ in CSF1R- or CD11c-expressing cells suppresses tumor growth. </p>
<p>Figure S3. Lipid import from myeloid cells in the TME.</p>
<p>Figure S9: Statins inhibit EGFRmutant tumor cell growth and oncogenic signaling.</p>
<p>Figure S7: PPARγ antagonist GW9662 rewires Alveolar macrophage metabolism within the TME.</p>
<p>Figure S2: Innate immune cells are regulated by GM-CSF and contributes to tumorigenesis.</p>
<div>Abstract<p>The limited efficacy of currently approved immunotherapies in EGFR-driven lung adenocarcinoma (LUAD) underscores the need to better understand alternative mechanisms governing local immunosuppression fuel novel therapies. Elevated surfactant and GM-CSF secretion from transformed epithelium induces tumor-associated alveolar macrophage (TA-AM) proliferation, which supports tumor growth by rewiring inflammatory functions lipid metabolism. TA-AM properties are driven...
<p>Figure S5: PPARγ Antagonist GW9662 modulates induces tumor regression and the TME.</p>
<p>Figure S4: Deficiency of PPARγ in CSF1R- or CD11c-expressing cells suppresses tumor growth. </p>