A5057014062- Lung Cancer Research Studies
- Lung Cancer Treatments and Mutations
- Lung Cancer Diagnosis and Treatment
- Cellular Mechanics and Interactions
- Microtubule and mitosis dynamics
- Signaling Pathways in Disease
- Immunotherapy and Immune Responses
- Monoclonal and Polyclonal Antibodies Research
- RNA modifications and cancer
- Neuroendocrine Tumor Research Advances
- Peptidase Inhibition and Analysis
- Bacteriophages and microbial interactions
- Cell Adhesion Molecules Research
- Epigenetics and DNA Methylation
- Cancer-related Molecular Pathways
- Advanced biosensing and bioanalysis techniques
- Chromatin Remodeling and Cancer
- Cancer Genomics and Diagnostics
- Ubiquitin and proteasome pathways
- Cancer, Hypoxia, and Metabolism
- Fungal Infections and Studies
- Force Microscopy Techniques and Applications
- Pancreatic function and diabetes
- Multiple Myeloma Research and Treatments
- Cancer Immunotherapy and Biomarkers
Dana-Farber Cancer Institute
2014-2025
Brigham and Women's Hospital
2014-2025
Harvard University
2015-2025
Dana-Farber Brigham Cancer Center
2015-2025
Boston Medical Center
2024
Massachusetts General Hospital
2015
Albert Einstein College of Medicine
2007-2011
Yeshiva University
2009-2011
Yale University
2011
Massachusetts Institute of Technology
2007
Invadopodia are matrix-degrading membrane protrusions in invasive carcinoma cells. The mechanisms regulating invadopodium assembly and maturation not understood. We have dissected the stages of show that invadopodia use cortactin phosphorylation as a master switch during these processes. In particular, was found to regulate cofilin Arp2/3 complex–dependent actin polymerization. Cortactin directly binds inhibits its severing activity. is required release this inhibition so can sever filaments...
Invasive carcinoma cells use specialized actin polymerization-driven protrusions called invadopodia to degrade and possibly invade through the extracellular matrix (ECM) during metastasis. Phosphorylation of invadopodium protein cortactin is a master switch that activates maturation function. Cortactin was originally identified as hyperphosphorylated in v-Src-transformed cells, but kinase or kinases are directly responsible for phosphorylation remain unknown. In this study, we provide...
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...
Abstract Although circulating tumor DNA (ctDNA) assays are increasingly used to inform clinical decisions in cancer care, they have limited ability identify the transcriptional programs that govern phenotypes and their dynamic changes during course of disease. To address these limitations, we developed a method for comprehensive epigenomic profiling from 1 ml patient plasma. Using an immunoprecipitation-based approach targeting histone modifications methylation, measured 1,268 profiles...
Invadopodia are invasive protrusions with proteolytic activity uniquely found in tumor cells. Cortactin phosphorylation is a key step during invadopodia maturation, regulating Nck1 binding and cofilin activity. The precise mechanism of cortactin-dependent regulation the roles this pathway maturation cell invasion not fully understood. We provide evidence that cortactin–cofilin regulated by local pH changes at mediated sodium–hydrogen exchanger NHE1. Furthermore, cortactin tyrosine mediates...
Invadopodia are matrix-degrading membrane protrusions in invasive carcinoma cells enriched proteins that regulate actin polymerization. The on-off regulatory switch initiates polymerization invadopodia requires phosphorylation of tyrosine residues 421, 466, and 482 on cortactin. However, it is unknown which these cortactin sites control We investigated the contribution individual (421, 482) to regulation invadopodia. provide evidence tyrosines 421 but not 482, required for generation free...
Abstract Small cell lung cancer (SCLC) accounts for 15% of cancers and is almost always linked to inactivating RB1 TP53 mutations. SCLC frequently responds, albeit briefly, chemotherapy. The canonical function the gene product repress E2F transcription factor family. also plays both E2F-dependent E2F-independent mitotic roles. We performed a synthetic lethal CRISPR/Cas9 screen in an RB1−/− line that conditionally expresses identify dependencies are caused by loss discovered lines...
More than 90% of small cell lung cancers (SCLCs) harbor loss-of-function mutations in the tumor suppressor gene RB1 . The canonical function product, pRB, is to repress E2F transcription factor family, but pRB also functions regulate cellular differentiation part through its binding histone demethylase KDM5A (also known as RBP2 or JARID1A). We show that promotes SCLC proliferation and SCLC's neuroendocrine phenotype by sustaining expression ASCL1. Mechanistically, we found sustains ASCL1...
Small cell lung cancers (SCLCs) are composed of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLCs, ∼12% all cases, uniquely dependent on POU2F3 itself; as such, approaches to attenuate expression may represent new therapeutic opportunities. Here using genome-scale screens for regulators SCLC proliferation, we define mSWI/SNF complexes top dependencies specific SCLC. Notably, chemical disruption ATPase activity...
Metastatic mammary carcinoma cells, which have previously been observed to form mature, matrix degrading invadopodia on a thick ECM matrix, are able with similar characteristics glass without applied matrix. They in response epidermal growth factor (EGF), and contain the usual invadopodium core proteins N-WASP, Arp2/3, cortactin, cofilin, F-actin. The study of allows for higher resolution analysis including use total internal reflection microscopy their relationship other cell motility...
Most intracellular proteins lack hydrophobic pockets suitable for altering their function with drug-like small molecules. Recent studies indicate that some undruggable can be targeted by compounds degrade them. For example, thalidomide-like drugs (IMiDs) the critical multiple myeloma transcription factors IKZF1 and IKZF3 recruiting them to cereblon E3 ubiquitin ligase. Current loss of signal ("down") assays identifying degraders often exhibit poor signal-to-noise ratios, narrow dynamic...
Some small cell lung cancers (SCLCs) are highly sensitive to inhibitors of the histone demethylase LSD1. LSD1 thought induce their anti-proliferative effects by blocking neuroendocrine differentiation, but mechanisms which controls SCLC phenotype not well understood. To identify genes required for inhibitor sensitivity in SCLC, we performed a positive selection genome-wide CRISPR/Cas9 loss function screen and found that ZFP36L1, an mRNA-binding protein destabilizes mRNAs, is sensitivity....
Despite small cell lung cancers (SCLCs) having a high mutational burden, programmed death-ligand 1 (PD-L1) immunotherapy only modestly increases survival. A subset of SCLCs that lose their ASCL1 neuroendocrine phenotype and restore innate immune signaling (termed the "inflammatory" subtype) have durable responses to PD-L1. Some are highly sensitive Aurora kinase inhibitors, but early-phase trials show short-lived responses, suggesting effective therapeutic combinations needed increase...