Section: Research

Arthur M. Mercurio, Ph.D.

Academic Role: Professor

Faculty Appointment(s) In:
   Cancer Biology

Research Interests

Mechanisms that underlie the genesis of invasive carcinoma and the progression to metastatic disease are the major interests of the Mercurio laboratory, with a specific focus on breast and colon carcinoma.  Given that all carcinomas arise from epithelia, our approach is rooted in the cell biology of mammary gland and colonic epithelia and it emphasizes understanding those changes in epithelial organization and function that contribute to invasive carcinoma.

Lab Projects

Epithelial-Mesenchymal Transition

The epithelial to mesenchymal transition (EMT) is a useful paradigm for studying the genesis of invasive carcinoma because it reflects events that occur at the invasive front of carcinomas and that persist in aggressive tumors.  The defining event for EMT is disruption of E-cadherin-mediated cell-cell adhesion, which results in loss of epithelial morphology and acquisition of a motile, mesenchymal phenotype.  We have established an ideal model system involving three-dimensional colonic organoids that can be induced to undergo a rapid EMT by cytokine stimulation.  The EMT involves transcriptional re-programming from an epithelial to a mesenchymal cell and we are pursuing mechanisms that underlie the transcriptional repression of epithelial genes (e.g., E-cadherin) and activation of mesencyhmal genes (N-cadherin). Given that the induction of cell migration and concomitant alterations in the cytoskeleton are key features of the EMT, we are also studying how integrin expression and function are regulated during the EMT and how they contribute to the behavior of post-EMT cells.   These studies are being performed in conjunction with experiments aimed at understanding the mechanism of how specific Rho family GTPases are regulated during the EMT.

The Integrin a6b4 and Invasive Carcinoma

This integrin, which is expressed primarily on the basal surface of most epithelia and in a few other cell types, is defined as an adhesion receptor for most of the known laminins, although increasing evidence indicates that it can signal independently of ligand (laminin) engagement. The distinguishing structural feature of  a6b4 is the atypical cytoplasmic domain of the b4 subunit. Two pairs of fibronectin type III repeats separated by a connecting segment characterize this domain and it is distinct both in size (approximately 1000aa) and structure from any other integrin subunit.  A primary function of  a6b4 is to maintain the integrity of epithelia through its ability to mediate the formation of stable and rigid adhesive structures termed hemidesmosomes on the basal cell surface that link the intermediate filament cytoskeleton with laminins in the basement membrane. Although the involvement of  a6b4 in hemidesmosome organization and function has dominated the study of this integrin, our lab pioneered studies that established that this integrin plays a pivotal role in functions associated with carcinoma progression, a role that is now widely accepted. What has emerged from these studies is the premise that  a6b4 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 the contribution of a6b4 to progression using mouse models and they are elucidating the mechanisms by which  a6b4 exerts its influence on cell functions linked to progression.

VEGF Signaling and Invasive Carcinoma
One important consequence of the EMT is that it facilitates the ability of carcinoma cells to survive in the absence of cell-cell contact and in the presence of stress imposed by the tumor microenvironment (e.g., hypoxia).  One mechanism for such survival that we have established is the elaboration of autocrine signaling loops as a consequence of EMT.  Specifically, we have shown that the expression of both VEGF and specific VEGF receptors (Neuropilin and Flt-1) is induced during the EMT and that a VEGF autocrine loop involving these receptors is essential for the survival of many carcinoma cells. In this direction, we are pursuing the signaling mechanisms by which Neuropilin and Flt-1 promote the survival of invasive carcinoma cells.

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

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