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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.
Andrea I. McClatchey, PhD Principal Investigator
Understanding morphogenesis and tumorigenesis
The 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, thereby both stabilizing membrane complexes and stiffening the cell cortex. The proximal goal of our work is to delineate the molecular function of Merlin and identify therapeutic targets for NF2; our 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 many tissues including the liver, kidney, intestine, skin and mammary gland. Molecular and cell-based studies suggest that these phenotypes are caused by defective organization of the cortical cytoskeleton, which leads to altered distribution of membrane receptors such as EGFR/ErbBs, cell junction components, and/or protein complexes that guide the orientation and function of the mitotic spindle. We also discovered that a fundamental function of Merlin is to restrict the distribution of Ezrin at the cell cortex and that loss of this activity underlies several of these phenotypes. In the absence of Merlin, as in NF2-mutant cancers, unrestricted cortical Ezrin drives both the aberrant distribution of membrane receptors such as EGFR/ErbBs and aberrant centrosome-to-cortex communication, yielding defective spindle orientation and integrity. These studies provided novel insight into how the organization of the cell cortex deﬁnes the identity and behavior of individual cell types and into how aberrant cortical organization contributes to unscheduled cell proliferation and tumor development.
Ongoing studies extend both basic and translational implications of this work. We are working to deﬁne the molecular mechanism by which Merlin/ERMs organize the biochemical and physical properties of the cell cortex and how this, in turn, controls receptor distribution and spindle orientation/ integrity. We are also working with our CCR colleague Dr. Shannon Stott to understand how Merlin/ERM activities and NF2-mutant phenotypes are inﬂuenced by mechanical forces such as those experienced in tissues. Importantly, we are also pursuing two novel translational avenues that stem directly from our basic studies:
1) The role of unregulated ErbB signaling in NF2-mutant tumors, particularly schwannomas, which are the hallmark of human NF2; and
2) Targeting aberrant centrosome/spindle function in NF2-mutant tumors; indeed, we have found that cells derived from all four major human NF2-mutant tumor types (schwannoma, meningioma, renal carcinoma and mesothelioma) exhibit centrosome/spindle defects and are extremely sensitive to centrosome/spindle-targeting drugs.
We believe that the continued partnering of these basic and translational studies will not only lead to novel therapeutic options for NF2-mutant tumors but also advance our understanding of these basic cellular activities that are known to contribute to other human cancers.
View a list of publications by researchers at the McClatchey Laboratory
Chiasson-MacKenzie C, Morris ZS, Baca Q, Morris BA, Coker JK, Mirchev R, Jensen AE, Carey T, Stott S, Golan DE, McClatchey AI. NF2/Merlin mediates contact-dependent inhibition of EGFR mobility and internalization via cortical actomyosin. J Cell Biol (in press).
Hebert AM, Duboff B, Casaletto JB, Gladden, AB, McClatchey AI. Merlin/ ERM proteins establish cortical asymmetry and centrosome position. Genes Dev. 26(24): 2709-23, 2012 Dec 15.
Casaletto JB, Saotome I, Curto M, McClatchey AI. Ezrin-mediated apical integrity is required for intestinal homeostasis. Proc Natl Acad Sci U S A. 108(29):11924-9, 2011 Jul 19.
Gladden AB, Hebert AM, Schneeberger EE, McClatchey AI. The NF2 tumor suppressor, Merlin, regulates epidermal development through the establishment of a junctional polarity complex. Dev Cell. 19(5):727-39, 2010 Nov 16.
Benhamouche S, Curto M, Saotome I, Gladden AB, Liu CH, Giovannini M, McClatchey AI. Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver. Genes Dev. 24(16):1718-30, 2010 Aug 15.
Morris ZS, McClatchey AI. Aberrant epithelial morphology and persistent epidermal growth factor receptor signaling in a mouse model of renal carcinoma. Proc Natl Acad Sci U S A. 106(24):9767-72, 2009 Jun 16.
Cole BK, Curto M, Chan AW, McClatchey AI. Localization to the cortical cytoskeleton is necessary for Nf2/merlin-dependent epidermal growth factor receptor silencing. Mol Cell Biol. 28(4):1274-84, 2008 Feb.
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