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1.
Cell ; 148(5): 896-907, 2012 Mar 02.
Article in English | MEDLINE | ID: mdl-22341455

ABSTRACT

To determine the role of telomere dysfunction and telomerase reactivation in generating pro-oncogenic genomic events and in carcinoma progression, an inducible telomerase reverse transcriptase (mTert) allele was crossed onto a prostate cancer-prone mouse model null for Pten and p53 tumor suppressors. Constitutive telomerase deficiency and associated telomere dysfunction constrained cancer progression. In contrast, telomerase reactivation in the setting of telomere dysfunction alleviated intratumoral DNA-damage signaling and generated aggressive cancers with rearranged genomes and new tumor biological properties (bone metastases). Comparative oncogenomic analysis revealed numerous recurrent amplifications and deletions of relevance to human prostate cancer. Murine tumors show enrichment of the TGF-ß/SMAD4 network, and genetic validation studies confirmed the cooperative roles of Pten, p53, and Smad4 deficiencies in prostate cancer progression, including skeletal metastases. Thus, telomerase reactivation in tumor cells experiencing telomere dysfunction enables full malignant progression and provides a mechanism for acquisition of cancer-relevant genomic events endowing new tumor biological capabilities.


Subject(s)
Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Telomerase/metabolism , Telomere/metabolism , Animals , Bone Neoplasms/secondary , Cell Line, Tumor , Crosses, Genetic , DNA Copy Number Variations , Disease Models, Animal , Female , Genomic Instability , Humans , Male , Mice , Tumor Suppressor Protein p53/metabolism
2.
Cell ; 149(3): 656-70, 2012 Apr 27.
Article in English | MEDLINE | ID: mdl-22541435

ABSTRACT

Tumor maintenance relies on continued activity of driver oncogenes, although their rate-limiting role is highly context dependent. Oncogenic Kras mutation is the signature event in pancreatic ductal adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible Kras(G12D)-driven PDAC mouse model establishes that advanced PDAC remains strictly dependent on Kras(G12D) expression. Transcriptome and metabolomic analyses indicate that Kras(G12D) serves a vital role in controlling tumor metabolism through stimulation of glucose uptake and channeling of glucose intermediates into the hexosamine biosynthesis and pentose phosphate pathways (PPP). These studies also reveal that oncogenic Kras promotes ribose biogenesis. Unlike canonical models, we demonstrate that Kras(G12D) drives glycolysis intermediates into the nonoxidative PPP, thereby decoupling ribose biogenesis from NADP/NADPH-mediated redox control. Together, this work provides in vivo mechanistic insights into how oncogenic Kras promotes metabolic reprogramming in native tumors and illuminates potential metabolic targets that can be exploited for therapeutic benefit in PDAC.


Subject(s)
Adenocarcinoma/metabolism , Disease Models, Animal , Pancreatic Neoplasms/metabolism , Proto-Oncogene Proteins p21(ras)/metabolism , Animals , Humans , Mice , Proto-Oncogene Proteins p21(ras)/genetics , Transcription, Genetic
3.
J Cell Sci ; 131(15)2018 08 10.
Article in English | MEDLINE | ID: mdl-30002137

ABSTRACT

Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that control a diverse range of biological processes during development and in adult tissues. We recently reported that somatic FGFR2 mutations are associated with shorter survival in endometrial cancer. However, little is known about how these FGFR2 mutations contribute to endometrial cancer metastasis. Here, we report that expression of the activating mutations FGFR2N550K and FGFR2Y376C in an endometrial cancer cell model induce Golgi fragmentation, and loss of polarity and directional migration. In mutant FGFR2-expressing cells, this was associated with an inability to polarise intracellular pools of FGFR2 towards the front of migrating cells. Such polarization defects were exacerbated in three-dimensional culture, where FGFR2 mutant cells were unable to form well-organised acini, instead undergoing exogenous ligand-independent invasion. Our findings uncover collective cell polarity and invasion as common targets of disease-associated FGFR2 mutations that lead to poor outcome in endometrial cancer patients.


Subject(s)
Cell Movement/physiology , Cell Polarity/physiology , Endometrial Neoplasms/metabolism , Receptor, Fibroblast Growth Factor, Type 2/metabolism , Biotinylation , Cell Line, Tumor , Cell Movement/genetics , Cell Polarity/genetics , Cell Proliferation/genetics , Cell Proliferation/physiology , Chemotaxis/genetics , Chemotaxis/physiology , Endometrial Neoplasms/genetics , Female , Fluorescent Antibody Technique , HEK293 Cells , Humans , Immunoblotting , Lentivirus/genetics , Mutation/genetics , Receptor, Fibroblast Growth Factor, Type 2/genetics
4.
J Biol Chem ; 293(22): 8439-8448, 2018 06 01.
Article in English | MEDLINE | ID: mdl-29669810

ABSTRACT

Pathways of human epidermal growth factor (EGF) receptors are activated upon ligand-dependent or -independent homo- or heterodimerization and their subsequent transphosphorylation. Overexpression of these receptors positively correlates with transphosphorylation rates and increased tumor growth rates. MEDI4276, an anti-human epidermal growth factor receptor 2 (HER2) biparatopic antibody-drug conjugate, has two paratopes within each antibody arm. One, 39S, is aiming at the HER2 site involved in receptor dimerization and the second, single chain fragment (scFv), mimicking trastuzumab. Here we present the cocrystal structure of the 39S Fab-HER2 complex and, along with biophysical and functional assays, determine the corresponding epitope of MEDI4276 and its underlying mechanism of action. Our results reveal that MEDI4276's uniqueness is based first on the ability of its 39S paratope to block HER2 homo- or heterodimerization and second on its ability to cluster the receptors on the surface of receptor-overexpressing cells.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Breast Neoplasms/drug therapy , Protein Multimerization , Receptor, ErbB-2/chemistry , Receptor, ErbB-2/metabolism , Trastuzumab/pharmacology , Amino Acid Sequence , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Crystallography, X-Ray , Female , Humans , Models, Molecular , Phosphorylation , Protein Conformation , Sequence Homology , Tumor Cells, Cultured
5.
Org Biomol Chem ; 16(3): 367-371, 2018 01 17.
Article in English | MEDLINE | ID: mdl-29264603

ABSTRACT

Most protein-protein interactions occur inside cells. Peptides can inhibit protein-protein interactions but tend not to enter cells. We systematically compare cell permeability for 8-12 residue model peptides with helix-inducing lactam/hydrocarbon linkers between amino acid sidechains. Cell uptake increases when hydrophobic residues and lactam linkers (i, i + 4) form a contiguous hydrophobic surface patch. Uptake increases further when both hydrophobic and positively charged (but not neutral or negative) residues are clustered into like surface patches. Amphipathicity alone is however insufficient for cell uptake of acyclic sequences. Changing the linker from lactam to hydrocarbon further increases uptake, but also promotes cell lysis. Helicity, positive charge and amphipathicity together promote cell permeability. Most known bioactive helical peptides do not optimally cluster residues for amphipathicity and so are likely unoptimised for cell uptake.


Subject(s)
Hydrophobic and Hydrophilic Interactions , Peptides/chemistry , Peptides/metabolism , Amino Acid Sequence , Biological Transport , HeLa Cells , Humans , Permeability , Protein Conformation, alpha-Helical
6.
Nature ; 470(7334): 359-65, 2011 Feb 17.
Article in English | MEDLINE | ID: mdl-21307849

ABSTRACT

Telomere dysfunction activates p53-mediated cellular growth arrest, senescence and apoptosis to drive progressive atrophy and functional decline in high-turnover tissues. The broader adverse impact of telomere dysfunction across many tissues including more quiescent systems prompted transcriptomic network analyses to identify common mechanisms operative in haematopoietic stem cells, heart and liver. These unbiased studies revealed profound repression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC-1α and PGC-1ß, also known as Ppargc1a and Ppargc1b, respectively) and the downstream network in mice null for either telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction is associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC-1α expression or germline deletion of p53 (also known as Trp53) substantially restores PGC network expression, mitochondrial respiration, cardiac function and gluconeogenesis. We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1α and PGC-1ß promoters, thereby forging a direct link between telomere and mitochondrial biology. We propose that this telomere-p53-PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.


Subject(s)
Mitochondria/metabolism , Mitochondria/pathology , Telomere/metabolism , Telomere/pathology , Adenosine Triphosphate/biosynthesis , Aging/metabolism , Aging/pathology , Animals , Cardiomyopathies/chemically induced , Cardiomyopathies/metabolism , Cardiomyopathies/pathology , Cardiomyopathies/physiopathology , Cell Proliferation , DNA, Mitochondrial/analysis , Doxorubicin/toxicity , Gluconeogenesis , Hematopoietic Stem Cells/metabolism , Hematopoietic Stem Cells/pathology , Liver/cytology , Liver/metabolism , Mice , Myocardium/cytology , Myocardium/metabolism , RNA/genetics , Reactive Oxygen Species/metabolism , Telomerase/deficiency , Telomerase/genetics , Telomere/enzymology , Telomere/genetics , Transcription Factors/antagonists & inhibitors , Transcription Factors/metabolism , Tumor Suppressor Protein p53/deficiency , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism
7.
Nature ; 470(7333): 269-73, 2011 Feb 10.
Article in English | MEDLINE | ID: mdl-21289624

ABSTRACT

Effective clinical management of prostate cancer (PCA) has been challenged by significant intratumoural heterogeneity on the genomic and pathological levels and limited understanding of the genetic elements governing disease progression. Here, we exploited the experimental merits of the mouse to test the hypothesis that pathways constraining progression might be activated in indolent Pten-null mouse prostate tumours and that inactivation of such progression barriers in mice would engender a metastasis-prone condition. Comparative transcriptomic and canonical pathway analyses, followed by biochemical confirmation, of normal prostate epithelium versus poorly progressive Pten-null prostate cancers revealed robust activation of the TGFß/BMP-SMAD4 signalling axis. The functional relevance of SMAD4 was further supported by emergence of invasive, metastatic and lethal prostate cancers with 100% penetrance upon genetic deletion of Smad4 in the Pten-null mouse prostate. Pathological and molecular analysis as well as transcriptomic knowledge-based pathway profiling of emerging tumours identified cell proliferation and invasion as two cardinal tumour biological features in the metastatic Smad4/Pten-null PCA model. Follow-on pathological and functional assessment confirmed cyclin D1 and SPP1 as key mediators of these biological processes, which together with PTEN and SMAD4, form a four-gene signature that is prognostic of prostate-specific antigen (PSA) biochemical recurrence and lethal metastasis in human PCA. This model-informed progression analysis, together with genetic, functional and translational studies, establishes SMAD4 as a key regulator of PCA progression in mice and humans.


Subject(s)
Disease Progression , Neoplasm Metastasis/pathology , Prostatic Neoplasms/pathology , Smad4 Protein/metabolism , Animals , Bone Morphogenetic Proteins/metabolism , Cell Proliferation , Cyclin D1/genetics , Cyclin D1/metabolism , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Genes, Tumor Suppressor/physiology , Humans , Lung Neoplasms/secondary , Lymphatic Metastasis , Male , Mice , Mice, Transgenic , Models, Biological , Neoplasm Invasiveness/genetics , Neoplasm Invasiveness/pathology , Neoplasm Metastasis/genetics , Osteopontin/genetics , Osteopontin/metabolism , PTEN Phosphohydrolase/deficiency , PTEN Phosphohydrolase/genetics , Penetrance , Prognosis , Prostate/metabolism , Prostate-Specific Antigen/metabolism , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/genetics , Smad4 Protein/deficiency , Smad4 Protein/genetics , Transforming Growth Factor beta
8.
J Chem Inf Model ; 55(6): 1181-91, 2015 Jun 22.
Article in English | MEDLINE | ID: mdl-26000704

ABSTRACT

Protease activated receptor 2 (PAR2) is an unusual G-protein coupled receptor (GPCR) involved in inflammation and metabolism. It is activated through cleavage of its N-terminus by proteases. The new N-terminus functions as a tethered ligand that folds back and intramolecularly activates PAR2, initiating multiple downstream signaling pathways. The only compounds reported to date to inhibit PAR2 activation are of moderate potency. Three structural models for PAR2 have been constructed based on sequence homology with known crystal structures for bovine rhodopsin, human ORL-1 (also called nociceptin/orphanin FQ receptor), and human PAR1. The three PAR2 model structures were compared and used to predict potential interactions with ligands. Virtual screening for ligands using the Chembridge database, and either ORL-1 or PAR1 derived PAR2 models led to identification of eight new small molecule PAR2 antagonists (IC50 10-100 µM). Notably, the most potent compound 1 (IC50 11 µM) was derived from the less homologous template protein, human ORL-1. The results suggest that virtual screening against multiple homology models of the same GPCR can produce structurally diverse antagonists and that this may be desirable even when some models have less sequence homology with the target protein.


Subject(s)
Drug Discovery/methods , Molecular Docking Simulation , Receptor, PAR-2/antagonists & inhibitors , Receptor, PAR-2/chemistry , Sequence Homology, Amino Acid , Animals , Binding Sites , Cattle , Cell Membrane/metabolism , Databases, Protein , Drug Evaluation, Preclinical , HT29 Cells , Humans , Ligands , Protein Structure, Tertiary , Receptor, PAR-2/metabolism
9.
Nature ; 455(7216): 1129-33, 2008 Oct 23.
Article in English | MEDLINE | ID: mdl-18948956

ABSTRACT

Glioblastoma (GBM) is a highly lethal brain tumour presenting as one of two subtypes with distinct clinical histories and molecular profiles. The primary GBM subtype presents acutely as a high-grade disease that typically harbours mutations in EGFR, PTEN and INK4A/ARF (also known as CDKN2A), and the secondary GBM subtype evolves from the slow progression of a low-grade disease that classically possesses PDGF and TP53 events. Here we show that concomitant central nervous system (CNS)-specific deletion of p53 and Pten in the mouse CNS generates a penetrant acute-onset high-grade malignant glioma phenotype with notable clinical, pathological and molecular resemblance to primary GBM in humans. This genetic observation prompted TP53 and PTEN mutational analysis in human primary GBM, demonstrating unexpectedly frequent inactivating mutations of TP53 as well as the expected PTEN mutations. Integrated transcriptomic profiling, in silico promoter analysis and functional studies of murine neural stem cells (NSCs) established that dual, but not singular, inactivation of p53 and Pten promotes an undifferentiated state with high renewal potential and drives increased Myc protein levels and its associated signature. Functional studies validated increased Myc activity as a potent contributor to the impaired differentiation and enhanced renewal of NSCs doubly null for p53 and Pten (p53(-/-) Pten(-/-)) as well as tumour neurospheres (TNSs) derived from this model. Myc also serves to maintain robust tumorigenic potential of p53(-/-) Pten(-/-) TNSs. These murine modelling studies, together with confirmatory transcriptomic/promoter studies in human primary GBM, validate a pathogenetic role of a common tumour suppressor mutation profile in human primary GBM and establish Myc as an important target for cooperative actions of p53 and Pten in the regulation of normal and malignant stem/progenitor cell differentiation, self-renewal and tumorigenic potential.


Subject(s)
Brain Neoplasms/pathology , Cell Differentiation , Glioma/pathology , Neoplastic Stem Cells/pathology , Neurons/pathology , PTEN Phosphohydrolase/metabolism , Tumor Suppressor Protein p53/metabolism , Animals , Brain Neoplasms/genetics , Cell Proliferation , Gene Expression Regulation , Glioblastoma/genetics , Glioblastoma/pathology , Glioma/genetics , Humans , Immunohistochemistry , Mice , Neoplastic Stem Cells/metabolism , Neurons/metabolism , PTEN Phosphohydrolase/genetics , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , Tumor Suppressor Protein p53/genetics
10.
Proc Natl Acad Sci U S A ; 108(49): E1275-84, 2011 Dec 06.
Article in English | MEDLINE | ID: mdl-22084065

ABSTRACT

Preclinical trials in mice represent a critical step in the evaluation of experimental therapeutics. Genetically engineered mouse models (GEMMs) represent a promising platform for the evaluation of drugs, particularly those targeting the tumor microenvironment. We evaluated sunitinib, an angiogenesis inhibitor that targets VEGF and PDGF receptor signaling, in two GEMMs of pancreatic cancer. Sunitinib did not reduce tumor burden in pancreatic ductal adenocarcinoma (PDAC), whereas tumor burden was reduced in the pancreatic neuroendocrine tumor (PNET) model, the latter results confirming and extending previous studies. To explore the basis for the lack of pathologic response in PDAC, we used noninvasive microbubble contrast-enhanced ultrasound imaging, which revealed that sunitinib reduced blood flow both in PDAC and in PNET, concomitant with a reduction in vessel density; nevertheless, PDAC tumors continued to grow, whereas PNET were growth impaired. These results parallel the response in humans, where sunitinib recently garnered FDA and European approval in PNET, whereas two antiangiogenic drugs failed to demonstrate efficacy in PDAC clinical trials. The demonstration of on-target activity but with discordant benefit in the PDAC and PNET GEMMs illustrates the potential value of linked preclinical and clinical trials.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Carcinoma, Pancreatic Ductal/drug therapy , Indoles/therapeutic use , Neuroendocrine Tumors/drug therapy , Pancreatic Neoplasms/drug therapy , Pyrroles/therapeutic use , Animals , Antigens, CD34/metabolism , Blood Flow Velocity/drug effects , Carcinoma, Pancreatic Ductal/diagnostic imaging , Carcinoma, Pancreatic Ductal/genetics , Clinical Trials as Topic , Contrast Media , Drug Evaluation, Preclinical , Humans , Immunohistochemistry , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Microbubbles , Neuroendocrine Tumors/diagnostic imaging , Neuroendocrine Tumors/genetics , Pancreas/blood supply , Pancreas/drug effects , Pancreas/metabolism , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/genetics , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Prognosis , Receptors, Platelet-Derived Growth Factor/metabolism , Sunitinib , Treatment Outcome , Tumor Burden/drug effects , Ultrasonography
11.
Org Lett ; 20(5): 1453-1456, 2018 03 02.
Article in English | MEDLINE | ID: mdl-29461066

ABSTRACT

The use of selenocysteines and various cross-linkers to induce helicity in a bioactive peptide is described. The higher reactivity of selenocysteine, relative to cysteine, facilitates rapid cross-linking within unprotected linear peptides under mild aqueous conditions. Alkylating agents of variable topology and electrophilicity were used to link pairs of selenocysteines within a p53 peptide. Facile selenoether formation enables diverse tailoring of the helical peptide structure.


Subject(s)
Cross-Linking Reagents/chemistry , Peptides/chemistry , Selenocysteine/chemistry , Alkylation , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Binding Sites , Cell Survival , Humans , MCF-7 Cells , Molecular Structure , Peptides/pharmacology , Protein Binding , Protein Conformation , Stereoisomerism , Surface Properties , Water
12.
ACS Chem Biol ; 12(8): 2051-2061, 2017 08 18.
Article in English | MEDLINE | ID: mdl-28636317

ABSTRACT

The oncogenic transcription factor activator protein-1 (AP-1) is a DNA-binding protein that assembles through dimerization of Fos and Jun protein subunits, their leucine-rich helical sequences entwining into a coiled-coil structure. This study reports on downsizing the proto-oncogene cFos protein (380 residues) to shorter peptides (37-25 residues) modified with helix-inducing constraints to enhance binding to Jun. A crystal structure is reported for a 37-residue Fos-derived peptide (FosW) bound to Jun. This guided iterative downsizing of FosW to shorter peptide sequences that were constrained into stable water-soluble α-helices by connecting amino acid side chains to form cyclic pentapeptide components. Structural integrity in the presence and absence of Jun was assessed by circular dichroism spectroscopy, while the thermodynamics of binding to cFos was measured by isothermal titration calorimetry. A 25-residue constrained peptide, one-third shorter yet 25% more helical than the structurally characterized 37-residue Fos-derived peptide, retained 80% of the binding free energy as a result of preorganization in a Jun-binding helix conformation, with the entropy gain (TΔS = +3.2 kcal/mol) compensating for the enthalpy loss. Attaching a cell-penetrating peptide (TAT48-57) and a nuclear localization signal (SV40) promoted cell uptake, localization to the nucleus, and inhibition of the proliferation of two breast cancer cell lines.


Subject(s)
Genes, jun , Peptides/chemistry , Proto-Oncogene Proteins c-fos/chemistry , Proto-Oncogenes , Amino Acid Sequence , Breast Neoplasms/therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Circular Dichroism , Female , Humans , Models, Molecular , Peptides/genetics , Peptides/pharmacology , Protein Binding , Proto-Oncogene Mas , Proto-Oncogene Proteins c-fos/genetics , Proto-Oncogene Proteins c-fos/pharmacology , Thermodynamics
13.
Cancer Cell ; 29(1): 117-29, 2016 Jan 11.
Article in English | MEDLINE | ID: mdl-26766593

ABSTRACT

Antibody-drug conjugate (ADC) which delivers cytotoxic drugs specifically into targeted cells through internalization and lysosomal trafficking has emerged as an effective cancer therapy. We show that a bivalent biparatopic antibody targeting two non-overlapping epitopes on HER2 can induce HER2 receptor clustering, which in turn promotes robust internalization, lysosomal trafficking, and degradation. When conjugated with a tubulysin-based microtubule inhibitor, the biparatopic ADC demonstrates superior anti-tumor activity over ado-trastuzumab emtansine (T-DM1) in tumor models representing various patient subpopulations, including T-DM1 eligible, T-DM1 ineligible, and T-DM1 relapsed/refractory. Our findings indicate that this biparatopic ADC has promising potential as an effective therapy for metastatic breast cancer and a broader patient population may benefit from this unique HER2-targeting ADC.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Immunotoxins/therapeutic use , Maytansine/analogs & derivatives , Receptor, ErbB-2/immunology , Trastuzumab/therapeutic use , Ado-Trastuzumab Emtansine , Animals , Breast Neoplasms/immunology , Female , Humans , Maytansine/therapeutic use , Mice , Treatment Outcome
15.
Cancer Cell ; 20(1): 92-103, 2011 Jul 12.
Article in English | MEDLINE | ID: mdl-21741599

ABSTRACT

Clinical and genomic evidence suggests that the metastatic potential of a primary tumor may be dictated by prometastatic events that have additional oncogenic capability. To test this "deterministic" hypothesis, we adopted a comparative oncogenomics-guided function-based strategy involving: (1) comparison of global transcriptomes of two genetically engineered mouse models with contrasting metastatic potential, (2) genomic and transcriptomic profiles of human melanoma, (3) functional genetic screen for enhancers of cell invasion, and (4) evidence of expression selection in human melanoma tissues. This integrated effort identified six genes that are potently proinvasive and oncogenic. Furthermore, we show that one such gene, ACP5, confers spontaneous metastasis in vivo, engages a key pathway governing metastasis, and is prognostic in human primary melanomas.


Subject(s)
Melanoma/genetics , Melanoma/pathology , Oncogenes/genetics , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Acid Phosphatase/genetics , Acid Phosphatase/metabolism , Animals , Cell Lineage/genetics , Conserved Sequence/genetics , Evolution, Molecular , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Genome/genetics , Humans , Isoenzymes/genetics , Isoenzymes/metabolism , Kaplan-Meier Estimate , Mice , Neoplasm Invasiveness , Neoplasm Metastasis , Neoplasm Staging , Phosphorylation , Reproducibility of Results , Tartrate-Resistant Acid Phosphatase , Tissue Array Analysis
16.
Cancer Discov ; 1(2): 158-69, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21984975

ABSTRACT

Initiation of pancreatic ductal adenocarcinoma (PDAC) is driven by oncogenic KRAS mutation, and disease progression is associated with frequent loss of tumor suppressors. In this study, human PDAC genome analyses revealed frequent deletion of the PTEN gene as well as loss of expression in primary tumor specimens. A potential role for PTEN as a haploinsufficient tumor suppressor is further supported by mouse genetic studies. The mouse PDAC driven by oncogenic Kras mutation and Pten deficiency also sustains spontaneous extinction of Ink4a expression and shows prometastatic capacity. Unbiased transcriptomic analyses established that combined oncogenic Kras and Pten loss promotes marked NF-κB activation and its cytokine network, with accompanying robust stromal activation and immune cell infiltration with known tumor-promoting properties. Thus, PTEN/phosphoinositide 3-kinase (PI3K) pathway alteration is a common event in PDAC development and functions in part to strongly activate the NF-κB network, which may serve to shape the PDAC tumor microenvironment.


Subject(s)
Adenocarcinoma/genetics , Carcinoma, Pancreatic Ductal/genetics , Cytokines/genetics , NF-kappa B/genetics , PTEN Phosphohydrolase/genetics , Pancreatic Neoplasms/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Animals , Animals, Genetically Modified , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/pathology , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Cytokines/metabolism , Genes, Tumor Suppressor , Humans , Mice , Mice, Inbred C57BL , Mutation , NF-kappa B/metabolism , PTEN Phosphohydrolase/metabolism , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism
17.
Cancer Cell ; 17(5): 497-509, 2010 May 18.
Article in English | MEDLINE | ID: mdl-20478531

ABSTRACT

A hallmark feature of glioblastoma is its strong self-renewal potential and immature differentiation state, which contributes to its plasticity and therapeutic resistance. Here, integrated genomic and biological analyses identified PLAGL2 as a potent protooncogene targeted for amplification/gain in malignant gliomas. Enhanced PLAGL2 expression strongly suppresses neural stem cell (NSC) and glioma-initiating cell differentiation while promoting their self-renewal capacity upon differentiation induction. Transcriptome analysis revealed that these differentiation-suppressive activities are attributable in part to PLAGL2 modulation of Wnt/beta-catenin signaling. Inhibition of Wnt signaling partially restores PLAGL2-expressing NSC differentiation capacity. The identification of PLAGL2 as a glioma oncogene highlights the importance of a growing class of cancer genes functioning to impart stem cell-like characteristics in malignant cells.


Subject(s)
Cell Differentiation/physiology , DNA-Binding Proteins/physiology , Glioblastoma/pathology , RNA-Binding Proteins/physiology , Signal Transduction/physiology , Stem Cells/cytology , Transcription Factors/physiology , Wnt Proteins/metabolism , Animals , Cell Transformation, Neoplastic , Humans , Mice
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