A5065679671- Protein Kinase Regulation and GTPase Signaling
- Pancreatic and Hepatic Oncology Research
- Cancer Genomics and Diagnostics
- PI3K/AKT/mTOR signaling in cancer
- Renal and related cancers
- Endoplasmic Reticulum Stress and Disease
- Cell death mechanisms and regulation
- Cancer, Lipids, and Metabolism
- Microtubule and mitosis dynamics
- RNA modifications and cancer
- Melanoma and MAPK Pathways
- CRISPR and Genetic Engineering
- Ferroptosis and cancer prognosis
- Parkinson's Disease Mechanisms and Treatments
- Mechanisms of cancer metastasis
- Cellular transport and secretion
- Chemical Reactions and Isotopes
- Art, Politics, and Modernism
- Cancer Immunotherapy and Biomarkers
- Radiomics and Machine Learning in Medical Imaging
- Advanced biosensing and bioanalysis techniques
- Genetic Neurodegenerative Diseases
- Giambattista Vico and Joyce
- Neurological disorders and treatments
- Genetic factors in colorectal cancer
Harvard University
2014-2024
Brigham and Women's Hospital
2015-2024
Howard Hughes Medical Institute
2017-2024
University of North Carolina at Chapel Hill
2009-2023
Takeda (United States)
2013
UNC Lineberger Comprehensive Cancer Center
2010-2012
Communities In Schools of Orange County
2012
Segeberger Kliniken
2012
Rutgers Sexual and Reproductive Health and Rights
2009
Cellular senescence is a terminal stress-activated program controlled by the p53 and p16(INK4a) tumor suppressor proteins. A striking feature of senescence-associated secretory phenotype (SASP), pro-inflammatory response linked to promotion aging. We have identified transcription factor GATA4 as SASP regulator. stabilized in cells undergoing required for SASP. Normally, degraded p62-mediated selective autophagy, but this regulation suppressed during senescence, thereby stabilizing GATA4....
During tumorigenesis, tumors must evolve to evade the immune system and do so by disrupting genes involved in antigen processing presentation or up-regulating inhibitory checkpoint genes. We performed vivo CRISPR screens syngeneic mouse tumor models examine requirements for tumorigenesis both with without adaptive selective pressure. In each type tested, we found a marked enrichment loss of suppressor (TSGs) presence an relative immunocompromised mice. Nearly one-third TSGs showed...
Abstract Phase II clinical trials of mitogen-activated protein/extracellular signal-regulated kinase (ERK) (MEK) inhibitors are ongoing and ERK1/2 activation is frequently used as a biomarker. In light the mutational BRAF KRAS in colorectal cancer, Raf-MEK-ERK protein anticipated to be promising. Previous studies pancreatic cancer have found little correlation between BRAF/KRAS mutation status activation, suggesting that identifying biomarkers MEK inhibitor response may more challenging than...
The high frequency of RAS mutations in human cancers (33%) has stimulated intense interest the development anti-Ras inhibitors for cancer therapy. Currently, major focus these efforts is centered on components involved Ras downstream effector signaling. In particular, more than 40 Raf-MEK-ERK mitogen-activated protein kinase cascade and phosphoinositide 3-kinase-AKT-mTOR signaling networks are currently under clinical evaluation. However, complicated by fact that can utilize at least 9...
The heterogeneity of protein-rich inclusions and its significance in neurodegeneration is poorly understood. Standard patient-derived iPSC models develop neither reproducibly nor a reasonable time frame. Here, we developed screenable "inclusionopathy" utilizing piggyBac or targeted transgenes to rapidly induce CNS cells that express aggregation-prone proteins at brain-like levels. Inclusions their effects on cell survival were trackable single-inclusion resolution. Exemplar cortical neuron...
Current approaches to block KRAS oncogene function focus on inhibition of K-Ras downstream effector signaling. We evaluated the antitumor activity selumetinib (AZD6244, ARRY-142886), a potent and selective MEK1/2 inhibitor, panel colorectal carcinoma (CRC) cells found no mutant CRC cell anchorage-independent growth. Although AKT was elevated in cells, PI3K did impair growth MEK inhibitor-insensitive lines, concurrent treatment with not provide additional activity. Therefore, we speculated...
Activating mutations in the KRAS oncogene are highly prevalent tumors, especially those of colon, lung, and pancreas. To better understand genetic dependencies that K-Ras mutant cells rely upon for their growth, we employed whole-genome CRISPR loss-of-function screens two isogenic pairs cell lines. Since loss essential genes is uniformly toxic CRISPR-based screens, also developed a small hairpin RNA (shRNA) library targeting genes. These approaches uncovered large set proteins whose results...
Abstract Triple-negative breast cancer (TNBC) is responsible for a disproportionate number of patient deaths due to extensive molecular heterogeneity, high recurrence rates, and lack targeted therapies. Dysregulation the phosphoinositide 3-kinase (PI3K)/AKT pathway occurs in approximately 50% TNBC patients. Here, we performed genome-wide CRISPR/Cas9 screen with PI3Kα AKT inhibitors find targetable synthetic lethalities TNBC. Cholesterol homeostasis was identified as collateral vulnerability...
Our recent studies implicated key and distinct roles for the highly related RalA RalB small GTPases (82% sequence identity) in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis invasive metastatic growth, respectively. How may promote PDAC invasion metastasis has not been determined. In light of known Ral effector functions regulation actin organization secretion, we addressed a possible role formation invadopodia, actin-rich membrane protrusions that contribute to tissue matrix...
Significance The PD-1/PD-L1 immunoinhibitory axis plays a key role in immune evasion of cancer cells, and therapies targeting show high efficacy certain types. Understanding how drivers regulate surveillance will enable development novel therapeutic strategies cancer-mediated evasion, identification new biomarkers response. Here, we utilized genetic screening with curated library 500 tumor suppressor genes to identify cohesin subunits CTCF among the most significant suppressors PD-L1. We...
Our recent studies established essential and distinct roles for RalA RalB small GTPase activation in K-Ras mutant pancreatic ductal adenocarcinoma (PDAC) cell line tumorigencity, invasion, metastasis. However, the mechanism of Ral PDAC has not been determined. There are four highly related mammalian RalGEFs (RalGDS, Rgl1, Rgl2, Rgl3) that can serve as Ras effectors. Whether or they share overlapping functions K-Ras-mediated growth transformation explored. We found plasma membrane targeting...
Abstract ECT2 is an activator of RHO GTPases that essential for cytokinesis. In addition, was identified as oncoprotein when expressed ectopically in NIH/3T3 fibroblasts. However, oncogenic activation resulted from N-terminal truncation, and such truncated proteins have not been found patients with cancer. this study, we observed elevated expression full-length protein preneoplastic colon adenomas, driven by increased mRNA abundance associated APC tumor-suppressor loss. Elevated levels were...
The Bcr-Abl and Lyn protein tyrosine kinases have been separately linked to the emergence of imatinib resistance in patients with chronic myelogenous leukemia. We developed fluorescent sensors for these that are enzymatically photophysically distinct, allowing us simultaneously, yet separately, visualize kinase activities both Abl Lyn. Multicolor monitoring revealed an imatinib-resistant cell line (MYL-R) displays a remarkable 13-fold enhancement activity relative its imatinib-sensitive...
Ras-like (Ral) small GTPases are regulated downstream of Ras and the noncanonical Ral guanine nucleotide exchange factor (RalGEF) effector pathway. Despite RalA RalB sharing 82% sequence identity utilization shared proteins, their roles in normal neoplastic cell growth have been shown to be highly distinct. Here, we determined that function is by protein kinase Cα (PKCα) phosphorylation. We found phosphorylation on Ser-198 C-terminal membrane targeting resulted enhanced endomembrane...
Mutationally activated K-Ras can utilize a multitude of downstream effector proteins to promote oncogenesis. While the Raf and phosphoinositol 3-kinase pathways are best-studied validated, recent studies have established critical importance Ral guanine nucleotide exchange factor (RalGEF) activation RalA RalB small GTPases in cancer biology. Due evidence that RalGEF-Ral pathway is necessary for tumorigenic metastatic potential KRAS mutant pancreatic ductal adenocarcinoma (PDAC) tumor cells,...
Understanding the genetic control of human embryonic stem cell function is foundational for developmental biology and regenerative medicine. Here we describe an integrated genome-scale loss- gain-of-function screening approach to identify networks governing proliferation differentiation into three germ layers. We identified a deep link between pluripotency maintenance survival by showing that alterations cause dissolution simultaneously increase apoptosis resistance. discovered...
Abstract The high prevalence of KRAS mutations and importance the RalGEF–Ral pathway downstream activated K-ras in pancreatic ductal adenocarcinoma (PDAC) emphasize identifying novel methods by which to therapeutically target these pathways. It was recently demonstrated that phosphorylation RalA S194 Aurora A kinase (AAK) is critical for PDAC tumorigenesis. We sought evaluate AAK-selective inhibitor MLN8237 as a potential indirect anti-RalA–targeted therapy PDAC. used site-specific...