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Journal ArticleDOI

Access to the Nucleus and Functional Association with c-Myc Is Required for the Full Oncogenic Potential of ΔEGFR/EGFRvIII

01 Feb 2013-Journal of Biological Chemistry (American Society for Biochemistry and Molecular Biology)-Vol. 288, Iss: 5, pp 3428-3438
TL;DR: It is shown that blocking ΔEGFR access to the nucleus attenuates its tumorigenicity and, conversely, that promoting nuclear accumulation enhances this, providing the first in vivo evidence that the nuclear actions of Δ EGFR contribute strongly to its oncogenic function.
About: This article is published in Journal of Biological Chemistry.The article was published on 2013-02-01 and is currently open access. It has received 13 citations till now.
Citations
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Journal ArticleDOI
TL;DR: Five contemporary immunocompetent mouse models are reviewed, each of which offer a suitable platform for testing novel immunotherapeutic approaches for glioblastoma patients.
Abstract: Glioblastoma remains a lethal diagnosis with a 5-year survival rate of less than 10%. (NEJM 352:987-96, 2005) Although immunotherapy-based approaches are capable of inducing detectable immune responses against tumor-specific antigens, improvements in clinical outcomes are modest, in no small part due to tumor-induced immunosuppressive mechanisms that promote immune escape and immuno-resistance. Immunotherapeutic strategies aimed at bolstering the immune response while neutralizing immunosuppression will play a critical role in improving treatment outcomes for glioblastoma patients. In vivo murine models of glioma provide an invaluable resource to achieving that end, and their use is an essential part of the preclinical workup for novel therapeutics that need to be tested in animal models prior to testing experimental therapies in patients. In this article, we review five contemporary immunocompetent mouse models, GL261 (C57BL/6), GL26 (C57BL/6) CT-2A (C57BL/6), SMA-560 (VM/Dk), and 4C8 (B6D2F1), each of which offer a suitable platform for testing novel immunotherapeutic approaches.

179 citations


Cites background from "Access to the Nucleus and Functiona..."

  • ...Similar genetic derangements have been reported in human gliomas [67-69]....

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Journal ArticleDOI
TL;DR: Targeting both the nEGFR signaling pathway, through the inhibition of its nuclear transport, and the classical EGFR signaling pathways with cetuximab may be a viable approach for the treatment of patients with TNBC.
Abstract: Triple-negative breast cancer (TNBC) is a subclass of breast cancers (i.e., estrogen receptor–negative, progesterone receptor–negative, and HER2-negative) that have poor prognosis and very few identified molecular targets. Strikingly, a high percentage of TNBCs overexpresses the EGF receptor (EGFR), yet EGFR inhibition has yielded little clinical benefit. Over the last decade, advances in EGFR biology have established that EGFR functions in two distinct signaling pathways: (i) classical membrane-bound signaling and (ii) nuclear signaling. Previous studies have demonstrated that nuclear EGFR (nEGFR) can enhance resistance to anti-EGFR therapies and is correlated with poor overall survival in breast cancer. On the basis of these findings, we hypothesized that nEGFR may promote intrinsic resistance to cetuximab in TNBC. To examine this question, a battery of TNBC cell lines and human tumors were screened and found to express nEGFR. Knockdown of EGFR expression demonstrated that TNBC cell lines retained dependency on EGFR for proliferation, yet all cell lines were resistant to cetuximab. Furthermore, Src Family Kinases (SFKs) influenced nEGFR translocation in TNBC cell lines and in vivo tumor models, where inhibition of SFK activity led to potent reductions in nEGFR expression. Inhibition of nEGFR translocation led to a subsequent accumulation of EGFR on the plasma membrane, which greatly enhanced sensitivity of TNBC cells to cetuximab. Collectively, these data suggest that targeting both the nEGFR signaling pathway, through the inhibition of its nuclear transport, and the classical EGFR signaling pathway with cetuximab may be a viable approach for the treatment of patients with TNBC. Mol Cancer Ther; 13(5); 1356–68. ©2014 AACR .

53 citations


Cites background from "Access to the Nucleus and Functiona..."

  • ...5AandB); this suggests that the rate of nEGFRexport, via its nuclear export sequence (28), varies between cell lines....

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  • ...These nuclear functions have been linked to three parameters of tumor biology: (i) inverse correlation with overall survival innumerous cancers (15–20), (ii) resistance to therapeutic agents including radiation (12, 21–24), chemotherapy (12, 13, 24), and anti-EGFR therapies gefitinib (25) and cetuximab (26), and (iii) enhanced tumor growth (27, 28)....

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Journal Article
TL;DR: The emerging concept of the non-canonical roles of the EGFR family reveals an astonishing and elaborate scheme on the molecular functions of membrane RTKs, offering new insights into the receptor biology as well as the development of comprehensive therapeutic strategies in the future.
Abstract: Epidermal growth factor receptor (EGFR) and its family members are key players in both physiological and pathological settings for which they are well recognized as models for investigating the functions and regulations of other membrane receptor tyrosine kinases (RTKs) and serve as therapeutic targets critical to clinical need and fundamental research. The canonical view of the pivotal functions in the EGFR family has been well documented as being an initiator of signaling amplification cascades from the plasma membrane to different subcellular compartments via receptor endocytic trafficking, intermolecular interaction, and kinase-substrate reaction in a temporalspatial manner. However, several lines of evidence have identified non-canonical roles of the EGFR family, acting as a transcriptional factor and a chromatin regulator in the nucleus to regulate gene expression, DNA replication, and DNA damage repair. Moreover, the EGFR family can even exert its impact outside the host cell through exosomal vesicle secretion. The emerging concept of the non-canonical roles of the EGFR family reveals an astonishing and elaborate scheme on the molecular functions of membrane RTKs, offering new insights into the receptor biology as well as the development of comprehensive therapeutic strategies in the future.

42 citations


Cites background from "Access to the Nucleus and Functiona..."

  • ...In 2013, Bogler and colleagues performed a ChIP-Seq in conjunction with bioinformatics analysis to identify genomewide targets of EGFRvIII and demonstrated that nuclear EGFRvIII associates with c-Myc on E-box-containing promoters, driving oncogenic functions in glioblastoma cells [40]....

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  • ...[40] Gururaj AE, Gibson L, Panchabhai S, Bai M, Manyam G, Lu Y, Latha K, Rojas ML, Hwang Y, Liang S and Bogler O....

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Journal ArticleDOI
TL;DR: A previously unrecognized role for AXL is uncovered in regulating the nuclear translocation of EGFR and it is suggested that AXL-mediated SFK and NRG1 expression promote this process.
Abstract: The epidermal growth factor receptor (EGFR) is a therapeutic target in patients with various cancers. Unfortunately, resistance to EGFR-targeted therapeutics is common. Previous studies identified two mechanisms of resistance to the EGFR monoclonal antibody cetuximab. Nuclear translocation of EGFR bypasses the inhibitory effects of cetuximab, and the receptor tyrosine kinase AXL mediates cetuximab resistance by maintaining EGFR activation and downstream signaling. Thus, we hypothesized that AXL mediated the nuclear translocation of EGFR in the setting of cetuximab resistance. Cetuximab-resistant clones of non-small cell lung cancer in culture and patient-derived xenografts in mice had increased abundance of AXL and nuclear EGFR (nEGFR). Cellular fractionation analysis, super-resolution microscopy, and electron microscopy revealed that genetic loss of AXL reduced the accumulation of nEGFR. SRC family kinases (SFKs) and HER family ligands promote the nuclear translocation of EGFR. We found that AXL knockdown reduced the expression of the genes encoding the SFK family members YES and LYN and the ligand neuregulin-1 (NRG1). AXL knockdown also decreased the interaction between EGFR and the related receptor HER3 and accumulation of HER3 in the nucleus. Overexpression of LYN and NRG1 in cells depleted of AXL resulted in accumulation of nEGFR, rescuing the deficit induced by lack of AXL. Collectively, these data uncover a previously unrecognized role for AXL in regulating the nuclear translocation of EGFR and suggest that AXL-mediated SFK and NRG1 expression promote this process.

39 citations

Journal ArticleDOI
TL;DR: Opinions regarding the role that EGFRvIII plays in tumorigenesis and for tumor aggressiveness are clearly contradictory and, therefore, it is crucial to determine its mechanism of action, but also to unambiguously define its role at early and advanced cancer stages.
Abstract: Epidermal growth factor receptor variant III (EGFRvIII) seems to constitute the perfect therapeutic target for glioblastoma (GB), as it is specifically present on up to 28–30% of GB cells. In case of other tumor types, expression and possible role of this oncogene still remain controversial. In spite of EGFRvIII mechanism of action being crucial for the design of small active anticancer molecules and immunotherapies, i.e., CAR-T technology, it is yet to be precisely defined. EGFRvIII is known to be resistant to degradation, but it is still unclear whether it heterodimerizes with EGF-activated wild-type EGFR (EGFRWT) or homodimerizes (including covalent homodimerization). Constitutive kinase activity of this mutated receptor is relatively low, and some researchers even claim that a nuclear, but not a membrane function, is crucial for its activity. Based on the analyses of recurrent tumors that are often lacking EGFRvIII expression despite its initial presence in corresponding primary foci, this oncogene is suggested to play a marginal role during later stages of carcinogenesis, while even in primary tumors EGFRvIII expression is detected only in a small percentage of tumor cells, undermining the rationality of EGFRvIII-targeting therapies. On the other hand, EGFRvIII-positive cells are resistant to apoptosis, more invasive, and characterized with enhanced proliferation rate. Moreover, expression of this oncogenic receptor was also postulated to be a marker of cancer stem cells. Opinions regarding the role that EGFRvIII plays in tumorigenesis and for tumor aggressiveness are clearly contradictory and, therefore, it is crucial not only to determine its mechanism of action, but also to unambiguously define its role at early and advanced cancer stages.

39 citations

References
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Journal ArticleDOI
TL;DR: This work presents Model-based Analysis of ChIP-Seq data, MACS, which analyzes data generated by short read sequencers such as Solexa's Genome Analyzer, and uses a dynamic Poisson distribution to effectively capture local biases in the genome, allowing for more robust predictions.
Abstract: We present Model-based Analysis of ChIP-Seq data, MACS, which analyzes data generated by short read sequencers such as Solexa's Genome Analyzer. MACS empirically models the shift size of ChIP-Seq tags, and uses it to improve the spatial resolution of predicted binding sites. MACS also uses a dynamic Poisson distribution to effectively capture local biases in the genome, allowing for more robust predictions. MACS compares favorably to existing ChIP-Seq peak-finding algorithms, and is freely available.

13,008 citations


"Access to the Nucleus and Functiona..." refers methods in this paper

  • ...ChIP-enriched binding peaks were identified by Model-based analysis of ChIP-Seq (MACS) (26)....

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Journal ArticleDOI
TL;DR: The Genomic Regions Enrichment of Annotations Tool (GREAT) is developed to analyze the functional significance of cis-regulatory regions identified by localized measurements of DNA binding events across an entire genome.
Abstract: We developed the Genomic Regions Enrichment of Annotations Tool (GREAT) to analyze the functional significance of cis-regulatory regions identified by localized measurements of DNA binding events across an entire genome. Whereas previous methods took into account only binding proximal to genes, GREAT is able to properly incorporate distal binding sites and control for false positives using a binomial test over the input genomic regions. GREAT incorporates annotations from 20 ontologies and is available as a web application. Applying GREAT to data sets from chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-seq) of multiple transcription-associated factors, including SRF, NRSF, GABP, Stat3 and p300 in different developmental contexts, we recover many functions of these factors that are missed by existing gene-based tools, and we generate testable hypotheses. The utility of GREAT is not limited to ChIP-seq, as it could also be applied to open chromatin, localized epigenomic markers and similar functional data sets, as well as comparative genomics sets.

3,730 citations

Journal ArticleDOI
TL;DR: The recent confluence of advances in stem cell biology, cell signaling, genome and computational science and genetic model systems have revolutionized understanding of the mechanisms underlying the genetics, biology and clinical behavior of glioblastoma.
Abstract: Malignant astrocytic gliomas such as glioblastoma are the most common and lethal intracranial tumors. These cancers exhibit a relentless malignant progression characterized by widespread invasion throughout the brain, resistance to traditional and newer targeted therapeutic approaches, destruction of normal brain tissue, and certain death. The recent confluence of advances in stem cell biology, cell signaling, genome and computational science and genetic model systems have revolutionized our understanding of the mechanisms underlying the genetics, biology and clinical behavior of glioblastoma. This progress is fueling new opportunities for understanding the fundamental basis for development of this devastating disease and also novel therapies that, for the first time, portend meaningful clinical responses.

2,203 citations


"Access to the Nucleus and Functiona..." refers background in this paper

  • ...Expression of EGFR (also called EGFRvIII), the most common mutation of EGFR (1), correlates with advanced disease and resistance to therapy (2)....

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Journal ArticleDOI
TL;DR: It is demonstrated that sorting sequences by this p-value effectively combines the information present in multiple motifs, leading to highly accurate and sensitive sequence homology searches.
Abstract: Motivation: To illustrate an intuitive and statistically valid method for combining independent sources of evidence that yields a p-value for the complete evidence, and to apply it to the problem of detecting simultaneous matches to multiple patterns in sequence homology searches. Results: In sequence analysis, two or more (approximately) independent measures of the membership ofa sequence (or sequence region) in some class are often available. We would like to estimate the likelihood of the sequence being a member of the class in view ofall the available evidence. An example is estimating the significance of the observed match of a macromolecular sequence (DNA or protein) to a set of patterned (motifs) that characterize a biological sequence family. An intuitive way to do this is to express each piece of evidence as a p-value, and then use the product of these p-values as the measure of membership in the family. We derive a formula and algorithm (QFAST) for calculating the statistical distribution of the product of n independent p-values. We demonstrate that sorting sequences by this p-value effectively combines the information present in multiple motifs, leading to highly accurate and sensitive sequence homology searches.

1,194 citations

Journal ArticleDOI
TL;DR: Regulatable transgenic mouse models of oncogenesis have shed light on the role of c-MYC in tumour progression and provide hope for effective cancer therapies.
Abstract: Deregulated expression of c-MYC occurs in a broad range of human cancers and is often associated with poor prognosis, indicating a key role for this oncogene in tumour progression. However, as established human tumours often bear multiple genetic lesions, it is difficult to determine whether c-MYC is instrumental in the initiation/progression of the tumour, or indeed whether inactivating c-MYC would lead to tumour regression. Regulatable transgenic mouse models of oncogenesis have shed light on these issues and provide hope for effective cancer therapies.

1,142 citations


"Access to the Nucleus and Functiona..." refers background in this paper

  • ...c-Myc is known to bind to the E-box motifs enriched in our dataset (17) and has been implicated in gliomagenesis (38)....

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  • ...We identified that the E-box motif, which is the binding motif of the c-Myc/Max obligatory heterodimer (17), is enriched in EGFR targeted promoters....

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