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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 Regulation of mitogen-activated protein kinase activation by the cytoplasmic domain of the alpha6 integrin subunit.
Academic Article Integrin (alpha 6 beta 4) regulation of eIF-4E activity and VEGF translation: a survival mechanism for carcinoma cells.
Academic Article Malignant transformation of human cells by constitutive expression of platelet-derived growth factor-BB.
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 Metabolic stress induces the lysosomal degradation of neuropilin-1 but not neuropilin-2.
Academic Article Insulin receptor substrate-2 regulates aerobic glycolysis in mouse mammary tumor cells via glucose transporter 1.
Academic Article Transcriptional regulation of VEGF-A by the unfolded protein response pathway.
Academic Article Neuropilin-2 promotes branching morphogenesis in the mouse mammary gland.
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 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 Id2 complexes with the SNAG domain of Snai1 inhibiting Snai1-mediated repression of integrin ?4.
Academic Article Flt-1-dependent survival characterizes the epithelial-mesenchymal transition of colonic organoids.
Academic Article Regulation of alpha 6 beta 1 integrin laminin receptor function by the cytoplasmic domain of the alpha 6 subunit.
Academic Article Glycogen synthase kinase-3 is an endogenous inhibitor of Snail transcription: implications for the epithelial-mesenchymal transition.
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 Mobilization and activation of a signaling competent alpha6beta4integrin underlies its contribution to carcinoma progression.
Academic Article Non-angiogenic functions of VEGF in breast cancer.
Academic Article Regulation of beta 4-integrin expression by epigenetic modifications in the mammary gland and during the epithelial-to-mesenchymal transition.
Academic Article IAP regulation of metastasis.
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 ? sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription.
Academic Article Sucrase-isomaltase is an independent prognostic marker for colorectal carcinoma.
Academic Article Regulation of alpha 6 beta 1 integrin-mediated migration in macrophages.
Academic Article Regulation of cellular interactions with laminin by integrin cytoplasmic domains: the A and B structural variants of the alpha 6 beta 1 integrin differentially modulate the adhesive strength, morphology, and migration of macrophages.
Concept Up-Regulation
Concept Gene Expression Regulation, Developmental
Concept Gene Expression Regulation
Concept Gene Expression Regulation, Enzymologic
Concept Gene Expression Regulation, Neoplastic
Academic Article Orphan nuclear receptor TR3/Nur77 improves wound healing by upregulating the expression of integrin ?4.
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 Integrin ?4 regulation of PTHrP underlies its contribution to mammary gland development.
Academic Article ER? regulation of NF-kB activation in prostate cancer is mediated by HIF-1.
Academic Article P-Rex1 Promotes Resistance to VEGF/VEGFR-Targeted Therapy in Prostate Cancer.
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 The ?6?4 integrin promotes resistance to ferroptosis.
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.
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