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Search Results to Arthur M Mercurio PhD

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ACADEMIC BACKGROUND

Arthur Mercurio received his B.S. in Biochemistry from Rutgers University in 1975 and a Ph.D. in Cell Biology from Columbia University in 1981. He was a Postdoctoral Fellow in the Center for Cancer Research at M.I.T. from 1981-1985. In 1986, he joined the faculty at Harvard Medical School and the Beth Israel Deaconess Medical Center. He was the Director of the Division of Cancer Biology and Angiogenesis at BIDMC until 2005 when he became Vice Chairman of the Department of Cancer Biology at the University of Massachusetts Medical School and Interim Chair in 2010. Dr. Mercurio is a recipient of the American Cancer Society Junior Faculty and Faculty Research Awards, and he was an Honorary Professor at the University of Copenhagen.

TRANSLATIONAL CANCER CELL BIOLOGY

We are interested in the initiation and progression of epithelial-derived tumors (carcinomas), especially aggressive, poorly differentiated tumors. Our research projects emphasize molecular cell biology but they derive from the analysis and clinical behavior of carcinomas. Our goal is to identify mechanisms that account for the loss of differentiation and the highly aggressive behavior of these tumors, and to exploit these mechanisms to improve prognosis and therapy. Ongoing projects in the lab include studies on:

Regulation and Function of Integrins

The lab has a long-standing interest in the a6 integrins (a6ß1 and a6ß4). These integrins have pivotal roles in the biology of carcinomas as demonstrated by our work and that of others. The a6ß1 integrin (CD49f) is an established marker for many populations of tumor stem/initiating cells including those present in breast and prostate carcinomas and it is essential for the function of these cells. Current studies on a6ß1 involve its regulation by Neuropilin-2 and VEGF signaling (see below) and elucidating the mechanism by which it contributes to the function of tumor stem/initiating cells. We are continuing our studies on the integrin a6ß4 (referred to as ‘ß4 integrin’) in this context. The primary function of this integrin, which is expressed on the basal surface of most epithelia, is to anchor the epithelium to laminins in the basement membrane and maintain epithelial integrity. Our lab pioneered studies that established that this integrin also plays a significant role in functions associated with carcinoma progression, including migration, invasion and survival, and that it is often expressed in poorly differentiated carcinomas. What has emerged from these studies is the premise that the ß4 integrin plays a dominant role in progression through its ability to influence other receptors and key signaling pathways. Given these findings and their implications, current projects are assessing mechanisms that regulate ß4 integrin gene expression in human cancers, the role of specific microRNAs in regulating ß4 integrin function and signaling and the contribution of ß4 integrin to epithelial biology and carcinoma progression using mouse models of specific carcinomas.

VEGF Function and Signaling in Carcinoma Cells

This project is based on the hypothesis that VEGF receptors expressed on carcinoma cells mediate VEGF signaling and that VEGF signaling in epithelial cells contributes to tumor initiation. This hypothesis challenges the notion that the function of VEGF in cancer is limited to angiogenesis and that therapeutic approaches based on the inhibition of VEGF and its receptors target only angiogenesis. We are most interested in a specific class of VEGF receptors termed the neuropilins (NRPs). NRP1 and NRP2 were identified initially as neuronal receptors for semaphorins, but they also function as VEGF receptors on tumor cells. We are particularly interested in NRP2 because our recent findings indicate that its contribution to breast tumorigenesis is significant. NRP2 expression correlates with progression and poor outcome in women with breast cancer, and its expression is associated with aggressive, triple-negative breast cancers. Moreover, our data indicate that NRP2 expression is induced by oncogenic stimuli that promote mammary tumor formation and they suggest that it has a causal role in tumorigenesis. We also discovered that NRP2 is highly enriched in tumor-initiating cells isolated from triple-negative tumors and that it can regulate the function of the a6ß1 integrin (CD49f), a marker of tumor-initiating cells. An important implication of our findings is that NRP2 is a prime target for therapeutic intervention, a highly feasible possibility because function-blocking antibodies are available for clinical trials. This issue is timely because the FDA has recommended discontinuing the use of Avastin (bevacizumab) for treating breast cancer because it has not been shown to be effective. Bevacizumab, however, does not inhibit the VEGF/NRP2 interaction, strengthening the rationale for targeting NRP2 directly. Based on existing data, we postulate that VEGF/NRP2 signaling cooperates with oncogenic stimuli to drive the formation of breast cancers by promoting the functions of tumor-initiating cells, especially the function and signaling properties of the a6ß1 integrin.

We are also pursuing the contribution of VEGF/NRP2 to prostate cancer. This project is based on our novel findings that PTEN deletion induces JNK/Jun-dependent NRP2 expression, NRP2 contributes to the growth of PTEN-null prostate carcinoma cells in soft agar and as xenografts, and NRP2 expression correlates with Gleason grade. The role of VEGF/NRP2 signaling in prostate tumorigenesis can be explained by our exciting discovery that NRP2 facilitates the expression of Bmi-1, a transcriptional repressor that has a critical role in the function of prostate stem and tumor initiating cells. We have also shown that NRP2 suppresses the IGF-1 receptor (IGF-1R) by a mechanism that involves transcriptional repression by Bmi-1 and, as a consequence, confers resistance to IGF-1R therapy of prostate carcinoma. In fact, we have found that NRP2 expressing prostate tumors are resistant to IGF-1R therapy. This hypothesis is significant because several IGF-1R inhibitors are in clinical trials but the mechanisms to account for patient response to these inhibitors are largely unknown. Given that clinical trials of the VEGF Ab bevacizumab have been disappointing, we are targeting NRP2 directly on tumor cells in combination with IGF-1R inhibition as a novel and a potentially potent approach for treating prostate carcinoma.


Regulation of Epithelial Fate and Carcinoma Differentiation by Estrogen Receptors
We are interested in the hypothesis that ligand-dependent activation of estrogen receptors (either ERa or ß) sustains epithelial differentiation and that loss of this activation in carcinomas contributes to a more de-differentiated, aggressive phenotype. This hypothesis is supported by the observation that ERa-negative breast carcinomas are typically less differentiated and more aggressive than ERa-positive tumors. Also, the loss of ERß in high-grade prostate carcinomas is also linked to de-differentiation and highly invasive behavior. We reported that a key function of ERß and its specific ligand 5a-androstane-3ß,17ß-diol (3ß-adiol) is to maintain an epithelial phenotype and repress mesenchymal characteristics in prostate carcinoma. The mechanism involves ERß-mediated destabilization of HIF-1a and transcriptional repression of HIF-1 target genes including VEGF-A. This mechanism is extremely important and relevant because we demonstrated that high Gleason grade tumors exhibit significantly elevated expression of HIF-1a but clinically relevant hypoxia is not seen in localized primary prostate cancer including high-grade tumors. These observations indicate that loss of ERß in prostate cancer mimics hypoxia by stabilizing HIF-1a. The mechanism by which ERß destabilizes HIF-1a is under investigation and we hypothesize that this mechanism is critical for maintaining an epithelial state and preventing a mesenchymal transition. The loss of ERß that characterizes high-grade, aggressive prostate cancer results in increased VEGF expression in tumor cells and consequent autocrine VEGF/NRP2 signaling as described above.


RNA Binding Proteins in Aggressive Carcinomas
This project is based on the finding that the expression of IGFII mRNA-binding protein 3 (IMP3) is associated with highly aggressive cancers, including triple-negative breast carcinomas. We are pursuing the hypothesis that IMP3 has an essential role in maintaining a de-differentiated state characteristic of high-grade tumors and that it functions in this capacity by interacting with and facilitating the expression of specific mRNAs whose proteins products promote epithelial de-differentiation.


One or more keywords matched the following items that are connected to Mercurio, Arthur

Item TypeName
Academic Article Activation of phosphoinositide 3-OH kinase by the alpha6beta4 integrin promotes carcinoma invasion.
Academic Article Endothelial cells assemble two distinct alpha6beta4-containing vimentin-associated structures: roles for ligand binding and the beta4 cytoplasmic tail.
Academic Article Cooperative signaling between alpha(6)beta(4) integrin and ErbB-2 receptor is required to promote phosphatidylinositol 3-kinase-dependent invasion.
Academic Article Association between sucrase-isomaltase and p53 expression in colorectal cancer.
Academic Article Vascular endothelial growth factor is an autocrine survival factor for neuropilin-expressing breast carcinoma cells.
Academic Article Regulation of mitogen-activated protein kinase activation by the cytoplasmic domain of the alpha6 integrin subunit.
Academic Article Expression of the beta 4 integrin subunit induces monocytic differentiation of 32D/v-Abl cells.
Academic Article Integrin (alpha 6 beta 4) regulation of eIF-4E activity and VEGF translation: a survival mechanism for carcinoma cells.
Academic Article ADAM12/syndecan-4 signaling promotes beta 1 integrin-dependent cell spreading through protein kinase Calpha and RhoA.
Academic Article Invasive skin carcinoma--Ras and alpha6beta4 integrin lead the way.
Academic Article ADAM12 induces actin cytoskeleton and extracellular matrix reorganization during early adipocyte differentiation by regulating beta1 integrin function.
Academic Article Evidence that distinct states of the integrin alpha6beta1 interact with laminin and an ADAM.
Academic Article Competing autocrine pathways involving alternative neuropilin-1 ligands regulate chemotaxis of carcinoma cells.
Academic Article Laminin binding proteins.
Academic Article The Met receptor and alpha 6 beta 4 integrin can function independently to promote carcinoma invasion.
Academic Article Hypoxia-induced vascular endothelial growth factor transcription and protection from apoptosis are dependent on alpha6beta1 integrin in breast carcinoma cells.
Academic Article Activation of p53 function in carcinoma cells by the alpha6beta4 integrin.
Academic Article The epithelial-mesenchymal transition of colon carcinoma involves expression of IL-8 and CXCR-1-mediated chemotaxis.
Academic Article Malignant transformation of human cells by constitutive expression of platelet-derived growth factor-BB.
Academic Article Protein kinase C-dependent mobilization of the alpha6beta4 integrin from hemidesmosomes and its association with actin-rich cell protrusions drive the chemotactic migration of carcinoma cells.
Academic Article p53 inhibits alpha 6 beta 4 integrin survival signaling by promoting the caspase 3-dependent cleavage of AKT/PKB.
Academic Article Hypoxia stimulates carcinoma invasion by stabilizing microtubules and promoting the Rab11 trafficking of the alpha6beta4 integrin.
Academic Article A role for ADAM12 in breast tumor progression and stromal cell apoptosis.
Academic Article RhoA function in lamellae formation and migration is regulated by the alpha6beta4 integrin and cAMP metabolism.
Academic Article Reciprocal regulation of RhoA and RhoC characterizes the EMT and identifies RhoC as a prognostic marker of colon carcinoma.
Academic Article Ras stimulation of E2F activity and a consequent E2F regulation of integrin alpha6beta4 promote the invasion of breast carcinoma cells.
Academic Article Laminin: multiple forms, multiple receptors.
Academic Article The alpha6beta4 integrin can regulate ErbB-3 expression: implications for alpha6beta4 signaling and function.
Academic Article The cleavage of Akt/protein kinase B by death receptor signaling is an important event in detachment-induced apoptosis.
Academic Article PDZ interaction sites in integrin alpha subunits. T14853, TIP/GIPC binds to a type I recognition sequence in alpha 6A/alpha 5 and a novel sequence in alpha 6B.
Academic Article Insulin receptor substrate-2 regulates aerobic glycolysis in mouse mammary tumor cells via glucose transporter 1.
Academic Article The alpha 6 beta 4 integrin and epithelial cell migration.
Academic Article Protein kinase A regulates Rac and is required for the growth factor-stimulated migration of carcinoma cells.
Academic Article Notes on the heterogeneity, circulation, and modification of membranes, with emphasis on secretory cells, photoreceptors, and the toad bladder.
Academic Article Transcriptional regulation of VEGF-A by the unfolded protein response pathway.
Academic Article miR-10b targets Tiam1: implications for Rac activation and carcinoma migration.
Academic Article Neuropilin-2 promotes branching morphogenesis in the mouse mammary gland.
Academic Article ADAM12 produced by tumor cells rather than stromal cells accelerates breast tumor progression.
Academic Article Role of JNK in mammary gland development and breast cancer.
Academic Article Regulation of IMP3 by EGFR signaling and repression by ERß: implications for triple-negative breast cancer.
Academic Article Integrin ß4 regulates SPARC protein to promote invasion.
Academic Article Enhancing integrin function by VEGF/neuropilin signaling: implications for tumor biology.
Academic Article Vascular endothelial growth factor promotes breast carcinoma invasion in an autocrine manner by regulating the chemokine receptor CXCR4.
Academic Article Disruption of oligosaccharide processing in murine tumor cells inhibits their susceptibility to lysis by activated mouse macrophages.
Academic Article GLI1 regulates a novel neuropilin-2/a6ß1 integrin based autocrine pathway that contributes to breast cancer initiation.
Academic Article IMP3 protein promotes chemoresistance in breast cancer cells by regulating breast cancer resistance protein (ABCG2) expression.
Academic Article Id2 complexes with the SNAG domain of Snai1 inhibiting Snai1-mediated repression of integrin ß4.
Academic Article Modulation of two distinct galactosyltransferase activities in populations of mouse peritoneal macrophages.
Academic Article Tumor necrosis factor-alpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids.
Academic Article Activation of mouse peritoneal macrophages alters the structure and surface expression of protein-bound lactosaminoglycans.
Academic Article Flt-1-dependent survival characterizes the epithelial-mesenchymal transition of colonic organoids.
Academic Article Carbohydrate-binding protein 35 is the major cell-surface laminin-binding protein in colon carcinoma.
Academic Article Membrane circulation in neurons and photoreceptors: some unresolved issues.
Academic Article Role of the E-cadherin/alpha-catenin complex in modulating cell-cell and cell-matrix adhesive properties of invasive colon carcinoma cells.
Academic Article Activation of the p21 pathway of growth arrest and apoptosis by the beta 4 integrin cytoplasmic domain.
Academic Article Role of E-cadherin in the response of tumor cell aggregates to lymphatic, venous and arterial flow: measurement of cell-cell adhesion strength.
Academic Article A novel structural variant of the human beta 4 integrin cDNA.
Academic Article Fimbrin localized to an insoluble cytoskeletal fraction is constitutively phosphorylated on its headpiece domain in adherent macrophages.
Academic Article Protein kinase C-alpha phosphorylation of specific serines in the connecting segment of the beta 4 integrin regulates the dynamics of type II hemidesmosomes.
Academic Article Contributions of the alpha6 integrins to breast carcinoma survival and progression.
Academic Article Carbohydrate-binding protein 35 (Mac-2), a laminin-binding lectin, forms functional dimers using cysteine 186.
Academic Article Functional analysis of the contribution of RhoA and RhoC GTPases to invasive breast carcinoma.
Academic Article Glycogen synthase kinase-3 is an endogenous inhibitor of Snail transcription: implications for the epithelial-mesenchymal transition.
Academic Article Deoxyribonucleic-binding homeobox proteins are augmented in human cancer.
Academic Article Mobilization and activation of a signaling competent alpha6beta4integrin underlies its contribution to carcinoma progression.
Academic Article Altered localization of p120 catenin during epithelial to mesenchymal transition of colon carcinoma is prognostic for aggressive disease.
Academic Article Intrinsic signaling functions of the beta4 integrin intracellular domain.
Academic Article The major non-integrin laminin binding protein of macrophages is identical to carbohydrate binding protein 35 (Mac-2).
Academic Article IAP regulation of metastasis.
Academic Article IMP3, a new biomarker to predict progression of cervical intraepithelial neoplasia into invasive cancer.
Academic Article Neuropilin-2 regulates a6ß1 integrin in the formation of focal adhesions and signaling.
Academic Article Paternal RLIM/Rnf12 is a survival factor for milk-producing alveolar cells.
Academic Article VEGF/neuropilin-2 regulation of Bmi-1 and consequent repression of IGF-IR define a novel mechanism of aggressive prostate cancer.
Academic Article Estrogen receptor ß sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription.
Academic Article Macrophage interactions with laminin: PMA selectively induces the adherence and spreading of mouse macrophages on a laminin substratum.
Academic Article Laminin expression in colorectal carcinomas varying in degree of differentiation.
Academic Article The alpha 6A beta 1 and alpha 6B beta 1 integrin variants signal differences in the tyrosine phosphorylation of paxillin and other proteins.
Academic Article Mouse egg integrin alpha 6 beta 1 functions as a sperm receptor.
Academic Article Decreased expression of Mac-2 (carbohydrate binding protein 35) and loss of its nuclear localization are associated with the neoplastic progression of colon carcinoma.
Academic Article Poorly differentiated colon carcinoma cell lines deficient in alpha-catenin expression express high levels of surface E-cadherin but lack Ca(2+)-dependent cell-cell adhesion.
Concept Proto-Oncogene Protein c-ets-1
Concept Parathyroid Hormone-Related Protein
Concept Membrane Proteins
Concept Inhibitor of Differentiation Protein 2
Concept Protein Binding
Concept Protein Subunits
Concept Protein Transport
Concept DNA-Binding Proteins
Concept Protein Processing, Post-Translational
Concept ADAM Proteins
Concept Muscle Proteins
Concept Ubiquitin-Protein Ligases
Concept Unfolded Protein Response
Concept Tumor Suppressor Protein p53
Concept Mitogen-Activated Protein Kinases
Concept Insulin Receptor Substrate Proteins
Concept Calcium-Calmodulin-Dependent Protein Kinases
Concept p38 Mitogen-Activated Protein Kinases
Concept Heterotrimeric GTP-Binding Proteins
Concept rho GTP-Binding Proteins
Concept Inhibitor of Differentiation Protein 1
Concept GTP-Binding Proteins
Concept Protein Kinase Inhibitors
Concept Ribosomal Protein S6 Kinases
Concept Mitogen-Activated Protein Kinase 1
Concept Carrier Proteins
Concept Protein Biosynthesis
Concept Protein Interaction Mapping
Concept Mitogen-Activated Protein Kinase 9
Concept Nuclear Proteins
Concept Recombinant Proteins
Concept Cyclic AMP-Dependent Protein Kinases
Concept Protein Kinases
Concept Protein-Serine-Threonine Kinases
Concept Extracellular Matrix Proteins
Concept Intracellular Signaling Peptides and Proteins
Concept rhoA GTP-Binding Protein
Concept Mitogen-Activated Protein Kinase 3
Concept Proto-Oncogene Proteins c-met
Concept Intercellular Signaling Peptides and Proteins
Concept Repressor Proteins
Concept rab GTP-Binding Proteins
Concept Protein Kinase C
Concept Proto-Oncogene Proteins c-akt
Concept Proteins
Concept Microtubule-Associated Proteins
Concept Proto-Oncogene Proteins c-sis
Concept Cytoskeletal Proteins
Concept Protein Structure, Tertiary
Concept Adaptor Proteins, Signal Transducing
Concept Proto-Oncogene Proteins c-myc
Concept Mitogen-Activated Protein Kinase 8
Concept Protein Multimerization
Concept ras Proteins
Concept Recombinant Fusion Proteins
Concept Inhibitor of Apoptosis Proteins
Concept Protein Stability
Concept Mitogen-Activated Protein Kinase 7
Concept Protein Kinase C-alpha
Concept Neoplasm Proteins
Concept Microfilament Proteins
Concept JNK Mitogen-Activated Protein Kinases
Concept I-kappa B Proteins
Concept Focal Adhesion Protein-Tyrosine Kinases
Concept rac GTP-Binding Proteins
Concept Protein Isoforms
Concept Oncogene Proteins v-abl
Concept Proto-Oncogene Proteins
Concept Nerve Tissue Proteins
Concept Tumor Suppressor Proteins
Concept RNA-Binding Proteins
Academic Article IMP3 expression is associated with poor outcome and epigenetic deregulation in intrahepatic cholangiocarcinoma.
Academic Article Regulated splicing of the a6 integrin cytoplasmic domain determines the fate of breast cancer stem cells.
Academic Article A laminin 511 matrix is regulated by TAZ and functions as the ligand for the a6Bß1 integrin to sustain breast cancer stem cells.
Academic Article Structural basis for VEGF-C binding to neuropilin-2 and sequestration by a soluble splice form.
Academic Article IMP3 promotes stem-like properties in triple-negative breast cancer by regulating SLUG.
Academic Article Integrin ß4 regulation of PTHrP underlies its contribution to mammary gland development.
Academic Article ERß regulation of NF-kB activation in prostate cancer is mediated by HIF-1.
Academic Article Tead and AP1 Coordinate Transcription and Motility.
Academic Article Cell clustering mediated by the adhesion protein PVRL4 is necessary for a6ß4 integrin-promoted ferroptosis resistance in matrix-detached cells.
Academic Article Insulin-Like Growth Factor 2 mRNA-Binding Protein 3 Modulates Aggressiveness of Ewing Sarcoma by Regulating the CD164-CXCR4 Axis.

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