Section: Research

Arthur M. Mercurio, Ph.D.

Academic Role: Professor

Faculty Appointment(s) In:
   Cancer Biology

Molecular Cell Biology of Tumor Progression

We are interested in understanding mechanisms that enable solid tumors (carcinomas) to invade surrounding tissue and progress to metastatic disease.  A central focus in the lab is the epithelial to mesenchymal transition (EMT). During this developmental process, epithelial cells, characterized by strong cell-cell junctions and apical-basal polarity, are transformed into mesenchymal cells, with reduced cell-cell interactions, a fibroblastic morphology and increased motility.  The EMT is recapitulated during the progression to invasive carcinoma and it has proven to be a useful paradigm for studying the mechanistic basis of invasive and metastatic carcinomas.   Using the EMT as a focal point, the lab is organized into three inter-related projects:

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. 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 epigenetic mechanisms that regulate β4 integrin gene expression in human cancers, the regulation of β4 integrin expression and function during the EMT, the role of specfic microRNAs (miRs) in regulating β4 integrin function and signaling and the contribution of β4 integrin to epithelial biology and carcinoma progression using mouse models of breast carcinoma.

VEGF Signaling, EMT 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 breast, colon and prostate carcinomas.

Nuclear Hormone Receptors and EMT

We are interested in the role of estrogen receptors (ERα and β) in regulating the EMT and invasive behavior, especially in prostate carcinoma. Recent studies have highlighted a role for ERα in regulating the EMT in breast cancer, but ERα and ERβ are different with respect to their expression and function. Interestingly there is an inverse relationship between the expression of ERβ1 and the progression of prostate carcinoma to highly invasive Gleason grades. Our recent data indicate that loss of ERβ1 expression triggers an EMT in both androgen-dependent and -independent prostate carcinoma cells that exhibit epithelial features, and that stimuli known to induce an EMT such as TGF-β and hypoxia extinguish ERβ1 expression.  We postulate that a quantitative loss of ERβ1 expression in prostate carcinoma, which parallels the progression to higher Gleason grades, results in the acquisition of EMT characteristics that contribute to invasive and aggressive behavior.  In other terms, ERβ1 functions as a ‘gatekeeper’ of the epithelial phenotype and a repressor of invasion.   The major hypothesis that we are pursuing is that ligand-dependent activation of ERβ1 sustains an epithelial phenotype and prevents an EMT by repressing VEGF transcription (see above).   Loss of ERβ1 expression enhances VEGF transcription and facilitates VEGF signaling that promotes a de-differentiated, aggressive phenotype characteristic of high Gleason grade tumors.

Office: 408
Phone: 508-856-8676
E-mail: Arthur.Mercurio@umassmed.edu

More on Arthur M. Mercurio's Research Research | Publications | Rotations | Biography View All Sections on One Page