McClatchey

McClatchey Lab

“The role of the membrane: cytoskeleton interface in receptor tyrosine kinase signaling, tissue morphogenesis and tumorigenesis...”

Overview

Andrea I. McClatchey, PhD

Professor of Pathology
Harvard Medical School

Principal Investigator
Massachusetts General Hospital Cancer Center

Overview

The McClatchey laboratory seeks to understand how cells organize their outer membrane or cortex, which, in turn, determines their identity, behavior, and interface with the external environment. Cancer cells exhibit defective membrane organization and therefore interact inappropriately with other cells and with their environment. Our research stems from a longstanding dedication to understanding the molecular basis of neurofibromatosis type 2 (NF2), a familial tumor syndrome 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 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 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. Cortical protein complexes 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 stems from our dedication to defining the molecular function of the NF2 protein Merlin, which, like the ERMs, can link membrane proteins to the cytoskeleton.

Through the generation of mouse models, we identified key roles for Merlin/ERMs in morphogenesis and tumorigenesis in many tissues. Molecular and cell-based studies suggest that these phenotypes are caused by defective distribution of membrane receptors such as EGFR/ErbBs, cell junctions and/or protein complexes that guide the orientation and function of the mitotic spindle. We also found that a key function of Merlin is to restrict the distribution of Ezrin. In the absence of Merlin, as in NF2-mutant cancers, unrestricted cortical Ezrin drives aberrant membrane receptor distribution and defective spindle orientation/integrity. These studies yield new insight into how the organization of the cell cortex drives normal cell behavior and how aberrant cortical organization contributes to unscheduled cell proliferation and tumorigenesis.

Ongoing studies extend basic and translational aspects of this work. A key goal is to define the molecular mechanism by which Merlin/ERMs organize the cell cortex and control receptor distribution and spindle orientation/integrity. We are also pursuing translational avenues for NF2-mutant tumors that stem directly from our basic studies such as targeting aberrant ErbB signaling or centrosome/spindle function. We believe that the continued partnering of basic and translational studies will lead to novel therapeutic options for NF2-mutant tumors and advance our understanding of how these basic cellular activities contribute to other human cancers.

Read the McClatchey Lab's Annual Report in Full

Group Members

Andrea I. McClatchey, PhD
Principal Investigator

  • Christine Chiasson-MacKenzie, Fellow
  • Thijs Koorman, Fellow
  • Evan O'Loughlin, PhD candidate, Harvard BBS
  • Ching-Hui Liu, Senior Research Technician
  • Will Bradford, Research Technician

Research Projects

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.

Selected Publications

View a list of publications by researchers at the McClatchey Laboratory

Selected Publications

Chiasson-MacKenzie C, Morris ZS, Basa Q, Morris B, Coker JK, Mirchev R, Jensen AE, Carey T, Stott SL, Golan DE, McClatchey AI. NF2/Merlin mediates contact-dependent inhibition of EGFR mobility and internalization via cortical actomyosin. J Cell Biol. 2015; 211(2):391-405 (with cover image and highlight).

Hebert AM, Duboff B, Casaletto JB, Gladden, AB, McClatchey AI. Merlin/ERM proteins establish cortical asymmetry and centrosome position. Genes Dev. 2012; 26(24):2709-23.

Casaletto JB, Saotome I, Curto M, McClatchey AI. Ezrin-mediated apical integrity is required for intestinal homeostasis. Proc Natl Acad Sci U S A. 2011; 108(29):11924-9.

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. 2010; 19(5):727-39.

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. 2010; 24(16):1718-30.

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. 2009; 106(24):9767-72.

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. 2008. 28(4):1274-84.

 

Contact

MGH Cancer Center
Massachusetts General Hospital
149 13th Street, 7th Floor
Charlestown, MA 02129
Phone: 617-726-5648
Fax: 617-724-6919
Email: mcclatch@helix.mgh.harvard.edu

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