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Andrea I. McClatchey, PhDProfessor of PathologyHarvard Medical SchoolPatricia and Scott Eston MGH Research Scholar
Assistant GeneticistCenter for Cancer Research
The McClatchey laboratory focuses on understanding how cells organize their outer membrane or cortex, which, in turn, determines their identity, behavior, and interface with the extracellular environment. Cancer cells exhibit defective membrane organization and therefore interact inappropriately with other cells and with their environment. Our research stems from a longstanding interest in understanding the molecular basis of neurofibromatosis type 2 (NF2), a familial cancer syndrome that is caused by mutation of the NF2 tumor suppressor gene. The NF2-encoded protein, Merlin, and closely related ERM proteins (Ezrin, Radixin, and Moesin) are key architects of the cell cortex.
Understanding morphogenesis and tumorigenesisThe vast array of forms and functions exhibited by different cell types is made possible by the organization of specialized domains within the cell cortex such as cell:cell and cell:matrix adhesions, the intestinal brush border, neuronal growth cone and immunological synapse. The assembly of such cortical domains involves the coordination of processes occurring at the plasma membrane with those in the underlying cytoskeleton. Central to this coordination is the formation of protein complexes at the plasma membrane that position membrane receptors, control their abundance and activity, and link them to the cortical cytoskeleton, thereby serving both regulatory and architectural functions. The overarching goal of my laboratory is to understand how the organization of protein complexes at the cell cortex contributes to morphogenesis and tumorigenesis. This interest stems from a longstanding dedication to elucidating the molecular basis of neurofibromatosis type 2 (NF2), a familial cancer syndrome that is caused by mutation of the NF2 tumor suppressor gene. The NF2-encoded protein Merlin is closely related to the ERM proteins (Ezrin, Radixin and Moesin) that link membrane proteins to the cortical cytoskeleton and is therefore a completely novel type of tumor suppressor. The proximal goal of our work is to delineate the molecular function of Merlin and to identify therapeutic targets for NF2; however, this work also directly addresses fundamental aspects of basic and cancer cell biology.
Through the generation and analysis of mouse models, we identified critical roles for Merlin and the ERM proteins in morphogenesis, homeostasis, and tumorigenesis in several tissues including the liver, kidney, intestine, skin and mammary gland. Complementary molecular and cell-based studies have revealed that these phenotypes may be attributable to defective cortical distribution of membrane receptors such as EGFR, cell junction components, and/or the mitotic spindle apparatus. We believe that each of these models reflects a unique biological context for studying how organization of the cell cortex defines the identity and behavior of individual cell types. Conversely, the study of each of these models will yield novel insight into how aberrant cortical organization contributes to unscheduled cell proliferation and to tumor development and progression.
Ongoing and future studies will extend both basic and translational implications of this work. From a basic perspective, we will further define the mechanism whereby Merlin/ERMs organize the cell cortex and control membrane receptor distribution and signaling. We are particularly interested in investigating how Merlin/ERMs define cortical architecture (i.e., by altering actin stability, contractility, etc.) and how Merlin/ERM distributions are regulated and utilized during mitosis or receptor endocytosis or during the creation of complex structures such as the cell junction. Another key goal is to define the repertoire of receptors (including other ErbB family members) whose distribution is controlled by Merlin/ERMs and to identify their major downstream signaling pathways (including the Hpo/Mst-Wts/Lats-Yki/Yap pathway).
A better understanding of cortical organization and spatiotemporal control of membrane complex assembly will fill a key gap in cancer biology. Many translational studies explore the efficacy of pharmacologic inhibitors of receptors such as EGFR in preclinical models while a large body of work explores the molecular and biochemical bases of ligand-dependent receptor activation and signaling. However, few studies consider that the distribution of receptors across the membrane (and therefore those that can/do respond to ligand or can be/are inhibited by pharmacologic agent) is heterogeneous and regulated. A key goal of our future work will be to provide new insights into the convergence of normal receptor signaling and therapeutic receptor targeting. Importantly, in this context we will continue to work toward our original and proximal goal of using basic mechanistic studies to identify and test therapeutic targets for NF2.
View a list of publications by researchers at the McClatchey Laboratory
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