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Xue Y.,Sloan Kettering Cancer Center | Xue Y.,Weill Cornell Rockefeller Sloan Kettering Tri Institutional MD PhD Program | Lito P.,Sloan Kettering Cancer Center
Clinical Cancer Research | Year: 2017

The ERK signaling pathway is one of the most commonly deregulated pathways in cancer. Assays that accurately measure ERK signaling output in clinical specimens would be extremely helpful not only in determining the pharmacodynamic effects of drug treatment but also in selecting those patients most likely to respond to therapy. © 2016 American Association for Cancer Research.


Oricchio E.,Sloan Kettering Cancer Center | Nanjangud G.,Sloan Kettering Cancer Center | Nanjangud G.,226 Rehab Center | Wolfe A.L.,Sloan Kettering Cancer Center | And 18 more authors.
Cell | Year: 2011

Insights into cancer genetics can lead to therapeutic opportunities. By cross-referencing chromosomal changes with an unbiased genetic screen we identify the ephrin receptor A7 (EPHA7) as a tumor suppressor in follicular lymphoma (FL). EPHA7 is a target of 6q deletions and inactivated in 72% of FLs. Knockdown of EPHA7 drives lymphoma development in a murine FL model. In analogy to its physiological function in brain development, a soluble splice variant of EPHA7 (EPHA7 TR) interferes with another Eph-receptor and blocks oncogenic signals in lymphoma cells. Consistent with this drug-like activity, administration of the purified EPHA7 TR protein produces antitumor effects against xenografted human lymphomas. Further, by fusing EPHA7 TR to the anti-CD20 antibody (rituximab) we can directly target this tumor suppressor to lymphomas in vivo. Our study attests to the power of combining descriptive tumor genomics with functional screens and reveals EPHA7 TR as tumor suppressor with immediate therapeutic potential. © 2011 Elsevier Inc.


Dow L.E.,Sloan Kettering Cancer Center | Dow L.E.,New York Medical College | Fisher J.,Sloan Kettering Cancer Center | O'Rourke K.P.,Sloan Kettering Cancer Center | And 7 more authors.
Nature Biotechnology | Year: 2015

CRISPR-Cas9-based genome editing enables the rapid genetic manipulation of any genomic locus without the need for gene targeting by homologous recombination. Here we describe a conditional transgenic approach that allows temporal control of CRISPR-Cas9 activity for inducible genome editing in adult mice. We show that doxycycline-regulated Cas9 induction enables widespread gene disruption in multiple tissues and that limiting the duration of Cas9 expression or using a Cas9D10A (Cas9n) variant can regulate the frequency and size of target gene modifications, respectively. Further, we show that this inducible CRISPR (iCRISPR) system can be used effectively to create biallelic mutation in multiple target loci and, thus, provides a flexible and fast platform to study loss-of-function phenotypes in vivo.


Dow L.E.,Sloan Kettering Cancer Center | Dow L.E.,New York Medical College | O'Rourke K.P.,Sloan Kettering Cancer Center | O'Rourke K.P.,Weill Cornell Rockefeller Sloan Kettering Tri Institutional MD PhD Program | And 6 more authors.
Cell | Year: 2015

The adenomatous polyposis coli (APC) tumor suppressor is mutated in the vast majority of human colorectal cancers (CRC) and leads to deregulated Wnt signaling. To determine whether Apc disruption is required for tumor maintenance, we developed a mouse model of CRC whereby Apc can be conditionally suppressed using a doxycycline-regulated shRNA. Apc suppression produces adenomas in both the small intestine and colon that, in the presence of Kras and p53 mutations, can progress to invasive carcinoma. In established tumors, Apc restoration drives rapid and widespread tumor-cell differentiation and sustained regression without relapse. Tumor regression is accompanied by the re-establishment of normal crypt-villus homeostasis, such that once aberrantly proliferating cells reacquire self-renewal and multi-lineage differentiation capability. Our study reveals that CRC cells can revert to functioning normal cells given appropriate signals and provide compelling in vivo validation of the Wnt pathway as a therapeutic target for treatment of CRC. © 2015 Elsevier Inc.


Coppo M.,Hospital for Special Surgery | Chinenov Y.,Hospital for Special Surgery | Sacta M.A.,Weill Cornell Rockefeller Sloan Kettering Tri Institutional MD PhD Program | Rogatsky I.,Hospital for Special Surgery | Rogatsky I.,Cornell University
Nature Communications | Year: 2016

Diet-induced obesity causes chronic macrophage-driven inflammation in white adipose tissue (WAT) leading to insulin resistance. WAT macrophages, however, differ in their origin, gene expression and activities: unlike infiltrating monocyte-derived inflammatory macrophages, WAT-resident macrophages counteract inflammation and insulin resistance, yet, the mechanisms underlying their transcriptional programming remain poorly understood. We recently reported that a nuclear receptor cofactor-glucocorticoid receptor (GR)-interacting protein (GRIP)1-cooperates with GR to repress inflammatory genes. Here, we show that GRIP1 facilitates macrophage programming in response to IL4 via a GR-independent pathway by serving as a coactivator for Kruppel-like factor (KLF)4-a driver of tissue-resident macrophage differentiation. Moreover, obese mice conditionally lacking GRIP1 in macrophages develop massive macrophage infiltration and inflammation in metabolic tissues, fatty livers, hyperglycaemia and insulin resistance recapitulating metabolic disease. Thus, GRIP1 is a critical regulator of immunometabolism, which engages distinct transcriptional mechanisms to coordinate the balance between macrophage populations and ultimately promote metabolic homeostasis. © The Author(s) 2016.


Griffioen K.J.,U.S. National Institute on Aging | Wan R.,U.S. National Institute on Aging | Brown T.R.,U.S. National Institute on Aging | Brown T.R.,Weill Cornell Rockefeller Sloan Kettering Tri Institutional MD PhD Program | And 5 more authors.
Neurobiology of Aging | Year: 2012

Huntington's disease (HD) is associated with profound autonomic dysfunction including dysregulation of cardiovascular control often preceding cognitive or motor symptoms. Brain-derived neurotrophic factor (BDNF) levels are decreased in the brains of HD patients and HD mouse models, and restoring BDNF levels prevents neuronal loss and extends survival in HD mice. We reasoned that heart rate changes in HD may be associated with altered BDNF signaling in cardiovascular control nuclei in the brainstem. Here we show that heart rate is elevated in HD (N171-82Q) mice at presymptomatic and early disease stages, and heart rate responses to restraint stress are attenuated. BDNF levels were significantly reduced in brainstem regions containing cardiovascular nuclei in HD mice and human HD patients. Central administration of BDNF restored the heart rate to control levels. Our findings establish a link between diminished BDNF expression in brainstem cardiovascular nuclei and abnormal heart rates in HD mice, and suggest a novel therapeutic target for correcting cardiovascular dysfunction in HD. © 2012.


Roy D.M.,Sloan Kettering Cancer Center | Roy D.M.,Weill Cornell Rockefeller Sloan Kettering Tri Institutional MD PhD Program | Walsh L.A.,Sloan Kettering Cancer Center | Chan T.A.,Sloan Kettering Cancer Center
Protein and Cell | Year: 2014

Epigenetic alterations are associated with all aspects of cancer, from tumor initiation to cancer progression and metastasis. It is now well understood that both losses and gains of DNA methylation as well as altered chromatin organization contribute significantly to cancer-associated phenotypes. More recently, new sequencing technologies have allowed the identification of driver mutations in epigenetic regulators, providing a mechanistic link between the cancer epigenome and genetic alterations. Oncogenic activating mutations are now known to occur in a number of epigenetic modifiers (i.e. IDH1/2, EZH2, DNMT3A), pinpointing epigenetic pathways that are involved in tumorigenesis. Similarly, investigations into the role of inactivating mutations in chromatin modifiers (i.e. KDM6A, CREBBP/EP300, SMARCB1) implicate many of these genes as tumor suppressors. Intriguingly, a number of neoplasms are defined by a plethora of mutations in epigenetic regulators, including renal, bladder, and adenoid cystic carcinomas. Particularly striking is the discovery of frequent histone H3.3 mutations in pediatric glioma, a particularly aggressive neoplasm that has long remained poorly understood. Cancer epigenetics is a relatively new, promising frontier with much potential for improving cancer outcomes. Already, therapies such as 5-azacytidine and decitabine have proven that targeting epigenetic alterations in cancer can lead to tangible benefits. Understanding how genetic alterations give rise to the cancer epigenome will offer new possibilities for developing better prognostic and therapeutic strategies. © 2014 The Author(s).


Chinenov Y.,Hospital for Special Surgery | Coppo M.,Hospital for Special Surgery | Gupte R.,Cell and Molecular Biology | Sacta M.A.,Weill Cornell Rockefeller Sloan Kettering Tri Institutional MD PhD Program | Rogatsky I.,Hospital for Special Surgery
BMC Genomics | Year: 2014

Background: Inflammation triggered by infection or injury is tightly controlled by glucocorticoid hormones which signal via a dedicated transcription factor, the Glucocorticoid Receptor (GR), to regulate hundreds of genes. However, the hierarchy of transcriptional responses to GR activation and the molecular basis of their oftentimes non-linear dynamics are not understood. Results: We investigated early glucocorticoid-driven transcriptional events in macrophages, a cell type highly responsive to both pro- and anti-inflammatory stimuli. Using whole transcriptome analyses in resting and acutely lipopolysaccharide (LPS)-stimulated macrophages, we show that early GR target genes form dense networks with the majority of control nodes represented by transcription factors. The expression dynamics of several glucocorticoid-responsive genes are consistent with feed forward loops (FFL) and coincide with rapid GR recruitment. Notably, GR binding sites in genes encoding members of the KLF transcription factor family colocalize with KLF binding sites. Moreover, our gene expression, transcription factor binding and computational data are consistent with the existence of the GR-KLF9-KLF2 incoherent FFL. Analysis of LPS-downregulated genes revealed striking enrichment in multimerized Zn-fingers- and KRAB domain-containing proteins known to bind nucleic acids and repress transcription by propagating heterochromatin. This raises an intriguing possibility that an increase in chromatin accessibility in inflammatory macrophages results from broad downregulation of negative chromatin remodelers. Conclusions: Pro- and anti-inflammatory stimuli alter the expression of a vast array of transcription factors and chromatin remodelers. By regulating multiple transcription factors, which propagate the initial hormonal signal, GR acts as a coordinating hub in anti-inflammatory responses. As several KLFs promote the anti-inflammatory program in macrophages, we propose that GR and KLFs functionally cooperate to curb inflammation. © 2014 Chinenov et al.; licensee BioMed Central Ltd.


Ramsey N.B.,Weill Cornell Rockefeller Sloan Kettering Tri Institutional MD PhD Program | Ramsey N.B.,Baylor College of Medicine | Andersen O.S.,Weill Cornell MedicalCollege
PLoS ONE | Year: 2015

Because of the perpetual development of resistance to current therapies for malaria, the Medicines for Malaria Venture developed the Malaria Box to facilitate the drug development process. We tested the 80 most potent compounds from the box for bilayer-mediated effects on membrane protein conformational changes (a measure of likely toxicity) in a gramicidinbased stopped flow fluorescence assay. Among the Malaria Box compounds tested, four compounds altered membrane properties (p< 0.05); MMV007384 stood out as a potent bilayer-perturbing compound that is toxic in many cell-based assays, suggesting that testing for membrane perturbation could help identify toxic compounds. In any case, MMV007384 should be approached with caution, if at all. © 2015 Ramsey, Andersen.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Huang Y.-H.,Weill Cornell Rockefeller Sloan Kettering Tri Institutional MD PhD Program
Journal of Religion and Health | Year: 2013

The proliferation of patents on human genes has raised important ethical questions centered on the conflict of patient rights and intellectual property rights. With the Supreme Court's June 2013 decision that altered the patent eligibility of genetic material, it is important to reexamine the ethical implications of gene patents as a concept. Such patents suggest an ownership of genetic material that may hinder access to healthcare and inhibit medical progress. The application of the current patent system to genetic material thus violates patients' rights without fulfilling the system's goal of promoting innovation, suggesting a need for a revised incentives infrastructure. © 2013 Springer Science+Business Media New York.

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