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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.

Rotation Projects

Rotation Projects

Rotation projects are designed to expose students to the molecular cell biology of solid tumors and to provide them with an appreciation for translational cancer research. Specific rotation projects, which are focused on the major themes of the lab, include:

Function and Regulation of Integrins (Cell Adhesion Receptors) in Cancer

  • Epigenetic mechanisms that regulate integrin gene expression in human cancers
  • Regulation of integrin expression and function during the EMT
  • Role of specfic microRNAs (miRs) in regulating integrin function and signaling
  • Contribution of integrins to carcinoma progression using mouse models of breast carcinoma

Vascular Endothelial Growth Factor (VEGF) Signaling, EMT and Carcinoma Progression

  • Function and expression of VEGF receptors in carcinoma cells
  • Regulation of VEGF transcription in response to EMT stimuli
  • Role of miRs in regulating VEGF receptors and signaling
  • Contribution of VEGF signaling to the behavior of aggressive, de-differentiated carcinomas

Nuclear Hormone Receptors and EMT

  • Role of estrogen receptors in regulating the EMT
  • Regulation of VEGF transcription by estrogen receptors
One or more keywords matched the following items that are connected to Mercurio, Arthur
Item TypeName
Academic Article Function of the integrin alpha 6 beta 1 in metastatic breast carcinoma cells assessed by expression of a dominant-negative receptor.
Academic Article Activation of phosphoinositide 3-OH kinase by the alpha6beta4 integrin promotes carcinoma invasion.
Academic Article Knockout of alpha6 beta1-integrin expression reverses the transformed phenotype of hepatocarcinoma cells.
Academic Article Release of cAMP gating by the alpha6beta4 integrin stimulates lamellae formation and the chemotactic migration of invasive carcinoma cells.
Academic Article A function for the integrin alpha6beta4 in the invasive properties of colorectal carcinoma cells.
Academic Article Towards a mechanistic understanding of tumor invasion--lessons from the alpha6beta 4 integrin.
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 The integrin alpha 6 beta 4 and the biology of carcinoma.
Academic Article Integrin laminin receptors and breast carcinoma progression.
Academic Article The integrin alpha 6 beta 1 promotes the survival of metastatic human breast carcinoma cells in mice.
Academic Article Integrin (alpha 6 beta 4) regulation of eIF-4E activity and VEGF translation: a survival mechanism for carcinoma cells.
Academic Article Lessons from the alpha2 integrin knockout mouse.
Academic Article Expression of enzymatically active sucrase-isomaltase is a ubiquitous property of colon adenocarcinomas.
Academic Article Invasive skin carcinoma--Ras and alpha6beta4 integrin lead the way.
Academic Article Competing autocrine pathways involving alternative neuropilin-1 ligands regulate chemotaxis of carcinoma cells.
Academic Article Use of RNA interference to inhibit integrin (alpha6beta4)-mediated invasion and migration of breast carcinoma cells.
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 The integrin alpha 6 beta 4 is a laminin receptor.
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 Human colon carcinoma cells use multiple receptors to adhere to laminin: involvement of alpha 6 beta 4 and alpha 2 beta 1 integrins.
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 The alpha6beta4 integrin can regulate ErbB-3 expression: implications for alpha6beta4 signaling and function.
Academic Article Analysis of integrin beta4 expression in human breast cancer: association with basal-like tumors and prognostic significance.
Academic Article Insulin receptor substrate-2 regulates aerobic glycolysis in mouse mammary tumor cells via glucose transporter 1.
Academic Article Protein kinase A regulates Rac and is required for the growth factor-stimulated migration of carcinoma cells.
Academic Article Traction forces mediated by alpha6beta4 integrin: implications for basement membrane organization and tumor invasion.
Academic Article miR-10b targets Tiam1: implications for Rac activation and carcinoma migration.
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 ER?: implications for triple-negative breast cancer.
Academic Article Integrin ?4 regulates SPARC protein to promote invasion.
Academic Article Sucrase-isomaltase: a marker associated with the progression of adenomatous polyps to adenocarcinomas.
Academic Article Vascular endothelial growth factor promotes breast carcinoma invasion in an autocrine manner by regulating the chemokine receptor CXCR4.
Academic Article Effects of ?4 integrin expression on microRNA patterns in breast cancer.
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/?6?1 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 VEGF targets the tumour cell.
Academic Article Carbohydrate-binding protein 35 is the major cell-surface laminin-binding protein in colon carcinoma.
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 E-selectin-mediated dynamic interactions of breast- and colon-cancer cells with endothelial-cell monolayers.
Academic Article Activation of the p21 pathway of growth arrest and apoptosis by the beta 4 integrin cytoplasmic domain.
Academic Article Autocrine signaling in carcinoma: VEGF and the alpha6beta4 integrin.
Academic Article Proteases, extracellular matrix, and cancer: a workshop of the path B study section.
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 Contributions of the alpha6 integrins to breast carcinoma survival and progression.
Academic Article Functional analysis of the contribution of RhoA and RhoC GTPases to invasive breast carcinoma.
Academic Article Transcriptional activation of integrin beta6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma.
Academic Article Deoxyribonucleic-binding homeobox proteins are augmented in human cancer.
Academic Article The epithelial-mesenchymal transition (EMT) and colorectal cancer progression.
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 The alpha6beta4 integrin maintains the survival of human breast carcinoma cells in vivo.
Academic Article Non-angiogenic functions of VEGF in breast cancer.
Academic Article Epithelial-mesenchymal transition and colorectal cancer: gaining insights into tumor progression using LIM 1863 cells.
Academic Article IAP regulation of metastasis.
Academic Article ERbeta impedes prostate cancer EMT by destabilizing HIF-1alpha and inhibiting VEGF-mediated snail nuclear localization: implications for Gleason grading.
Academic Article IMP3, a new biomarker to predict progression of cervical intraepithelial neoplasia into invasive cancer.
Academic Article Neuropilin-2 regulates ?6?1 integrin in the formation of focal adhesions and signaling.
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 Relationship between extracellular matrix interactions and degree of differentiation in human colon carcinoma cell lines.
Academic Article Interactions of human colorectal carcinoma cells with basement membranes. Analysis and correlation with differentiation.
Academic Article Laminin expression in colorectal carcinomas varying in degree of differentiation.
Academic Article Sucrase-isomaltase is an independent prognostic marker for colorectal carcinoma.
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 Expression of the alpha 6 beta 4 integrin by squamous cell carcinomas and basal cell carcinomas: possible relation to invasive potential?
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 Rectal Neoplasms
Concept Prostatic Neoplasms
Concept Neoplasms, Experimental
Concept Colorectal Neoplasms
Concept Bile Duct Neoplasms
Concept Neoplasms, Squamous Cell
Concept Liver Neoplasms
Concept Uterine Cervical Neoplasms
Concept Mammary Neoplasms, Experimental
Concept Breast Neoplasms
Concept Neoplasms
Concept Skin Neoplasms
Concept Colonic Neoplasms
Academic Article IMP3 expression is associated with poor outcome and epigenetic deregulation in intrahepatic cholangiocarcinoma.
Academic Article Regulated splicing of the ?6 integrin cytoplasmic domain determines the fate of breast cancer stem cells.
Academic Article A cell-ECM screening method to predict breast cancer metastasis.
Academic Article A laminin 511 matrix is regulated by TAZ and functions as the ligand for the ?6B?1 integrin to sustain breast cancer stem cells.
Academic Article Prostate tumorigenesis induced by PTEN deletion involves estrogen receptor ? repression.
Academic Article IMP3 promotes stem-like properties in triple-negative breast cancer by regulating SLUG.
Academic Article ER? regulation of NF-kB activation in prostate cancer is mediated by HIF-1.
Academic Article Highlights from the latest articles in nanomaterial-based therapies for targeting cancer stem cells.
Academic Article Tead and AP1 Coordinate Transcription and Motility.
Academic Article P-Rex1 Promotes Resistance to VEGF/VEGFR-Targeted Therapy in Prostate Cancer.
Academic Article Biochemical and biomechanical drivers of cancer cell metastasis, drug response and nanomedicine.
Academic Article VEGF-neuropilin-2 signaling promotes stem-like traits in breast cancer cells by TAZ-mediated repression of the Rac GAP ?2-chimaerin.
Academic Article IMP3 Stabilization of WNT5B mRNA Facilitates TAZ Activation in Breast Cancer.
Academic Article Rapid phenotyping of cancer stem cells using multichannel nanosensor arrays.
Academic Article Convergence of VEGF and YAP/TAZ signaling: Implications for angiogenesis and cancer biology.
Academic Article Cell clustering mediated by the adhesion protein PVRL4 is necessary for ?6?4 integrin-promoted ferroptosis resistance in matrix-detached cells.
Academic Article VEGF/Neuropilin Signaling in Cancer Stem Cells.
Academic Article CD44 splice isoform switching determines breast cancer stem cell state.
Academic Article The VEGF receptor neuropilin 2 promotes homologous recombination by stimulating YAP/TAZ-mediated Rad51 expression.
Academic Article Prominin2 Drives Ferroptosis Resistance by Stimulating Iron Export.
Academic Article Tumor cell-organized fibronectin maintenance of a dormant breast cancer population.
Academic Article Differentiation of Cancer Stem Cells through Nanoparticle Surface Engineering.
Academic Article Targeting prominin2 transcription to overcome ferroptosis resistance in cancer.
Academic Article O-linked ?2,3 sialylation defines stem cell populations in breast cancer.
Concept Triple Negative Breast Neoplasms
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  • Cancers