Academic Background

Art 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. Dr. Mercurio is a recipient of the American Cancer Society Junior Faculty and Faculty Research Awards, and he is an Honorary Professor at the University of Copenhagen. 

Mechanisms of Carcinoma Progression
From Bench to Bedside

We are interested in understanding mechanisms that enable epithelial-derived tumors (carcinomas) to invade surrounding tissue and progress to metastatic disease, with an emphasis on mechanisms that regulate epithelial and carcinoma differentiation.  The loss of epithelial differentiation in populations of carcinoma cells enhances their aggressive behavior and rate of progression.  Our research projects are based on the analysis and clinical behavior of poorly differentiated 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:

Integrin Function and Signaling

Although integrins (cell adhesion receptors) are expressed on both normal epithelial cells and carcinoma cells, their function and signaling properties can differ markedly and these properties contribute to tumor progression.  We are particularly interested in the integrin α6β4 (referred to as ‘β4 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 pivotal 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 β4 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 β4 integrin gene expression in human cancers, the role of specific microRNAs in regulating β4 integrin function and signaling and the contribution of β4 integrin to epithelial biology and carcinoma progression using mouse models of specific carcinomas. 

Epithelial-Mesenchymal Transition (EMT) in Carcinoma Differentiation and Progression

The EMT is a major focus of contemporary cancer research based on the hypothesis that the ability of epithelial-derived tumors to acquire mesenchymal characteristics is associated with more aggressive behavior and enhanced progression to metastatic disease.  An important caveat, however, is that not all de-differentiated tumors exhibit the hallmarks of a bona fide EMT.  Our work, for example, has demonstrated that de-differentiated tumors retain expression of some epithelial-specific proteins, especially those that are expressed during embryogenesis. A parallel hypothesis, therefore, is that carcinoma de-differentiation is a manifestation of embryonic gene expression.  Our studies in this area are aimed at evaluating and integrating these two hypotheses in the context of human carcinomas.

VEGF Signaling and Carcinoma Progression

The EMT facilitates the ability of carcinoma cells to invade and survive in the absence of cell-cell contacts and in the presence of stresses imposed by the tumor microenvironment (e.g., hypoxia).  One mechanism for such behavior that we have established is the elaboration of autocrine and paracrine signaling loops as a consequence of EMT.  Specifically, we have shown that the expression of both VEGF and specific VEGF receptors (Neuropilins and Flt-1) is induced during the EMT and that VEGF signaling in carcinoma cells involving these receptors is essential for progression. Current projects are assessing the function and expression of VEGF receptors in carcinoma cells, the mechanism by which VEGF transcription is regulated in response to EMT stimuli, the role of miRs in regulating VEGF receptors and signaling in carcinoma cells and the contribution of VEGF signaling to the behavior of highly aggressive, de-differentiated carcinomas.

Regulation of Epithelial Fate and Carcinoma Differentiation by Estrogen Receptors

We are interested in the hypothesis that ligand-dependent activation of estrogen receptors (either ERα or β) 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 ERα-negative breast carcinomas are typically less differentiated and more aggressive than ERα-positive tumors.  Also, the loss of ERβ in high-grade prostate carcinomas is also linked to de-differentiation and highly invasive behavior. We reported that a key function of ERβ and its specific ligand 5α-androstane-3β,17β-diol (3β-adiol) is to maintain an epithelial phenotype and repress mesenchymal characteristics in prostate carcinoma.  Stimuli (TGF-β and hypoxia) that induce an EMT diminish ERβ expression, and loss of ERβ is sufficient to promote an EMT.  The mechanism involves ERβ-mediated destabilization of HIF-1α and transcriptional repression of VEGF-A.  The VEGF-A receptor neuropilin-1 drives the EMT by promoting Snail1 nuclear localization. Importantly, this mechanism is manifested in high Gleason grade cancers, which exhibit significantly more HIF-1α and VEGF expression, and Snail1 nuclear localization in comparison to low Gleason grade cancers. Current projects include continued studies on the mechanism by which ERβ regulates differentiation in prostate carcinoma and studies on estrogenic regulation of oncofetal proteins in breast and prostate carcinoma.