McClatchey Lab

Research Summary

The McClatchey laboratory focuses on understanding how cells organize their outer surface – an important cellular compartment created by the interface between the cell membrane and underlying cortical cytoskeleton. This compartment governs the shape, identity and behavior of individual cells, as well as how they interact biochemically and mechanically with the extracellular environment. Normal cells modulate the features of the membrane:cytoskeleton interface to carry out key developmental processes and build functioning tissues. On the other hand, cancer cells exploit this compartment to interact inappropriately with other cells and with their environment during tumor initiation, invasion and metastasis. Our research stems from a longstanding quest to understand the molecular basis of a familial cancer syndrome caused by mutation of the neurofibromatosis type 2 (NF2) tumor suppressor gene. The NF2-encoded protein, Merlin, and closely related ERM proteins (Ezrin, Radixin and Moesin) are central architects of the cell cortex that have important roles in development and in many human cancers.

Research Projects

Understanding morphogenesis and tumorigenesis

The vast array of forms and functions exhibited by different cell types is enabled by the intrinsic organization of specialized domains within the cell cortex such as the leading edge of migratory cells, immunological synapse and microvillusstudded apical surfaces of epithelial cells. The spatial organization of individual cells, in turn, governs their organization into three dimensional structures that carry out organ-specific functions, such as the tubular networks of the lung, kidney, breast and liver and the heterotypic axoglial junction of peripheral nerves. The spatial organization of cortical domains in individual cells and tissues provides an essential layer of regulation to both biochemical and adhesive receptors on the cell surface. Alterations in cellular architecture are the earliest evidence of a developing tumor and signatures of tumor invasion and metastasis.

The assembly of cortical domains requires the coordination of processes occurring at the plasma membrane and underlying cytoskeleton. The overarching goal of my laboratory is to understand how the dynamic organization of this cellular compartment contributes to morphogenesis and tumorigenesis. We have focused particular attention on the neurofibromatosis type 2 (NF2) tumor suppressor, Merlin, and closely related ERM proteins (Ezrin, Radixin and Moesin) - membrane:cytoskeleton linking proteins that simultaneously influence membrane complexes and the cortical actomyosin cytoskeleton. The activities of Merlin/ERM proteins are critical for the morphogenesis of many tissues and have been implicated in many cancers.

Ongoing projects utilize mouse models, bioengineered 3D models and quantitative imaging to study the roles of Merlin/ ERM proteins in the morphogenesis of intrahepatic bile ducts in the liver and Schwann cell:axon relationships in peripheral nerves, and in the development of biliary and schwann cell tumors. Our studies have uncovered novel design principles that govern tissue morphogenesis and are hijacked by tumor-causing alterations, identified mechanisms by which aberrant cortical organization can drive intrinsic tumor heterogeneity, and yielded unexpected therapeutic targets and avenues of translation for cancer therapy.

It is increasingly clear that cancer fundamentally reflects the aberrant reenactment of developmental processes. We believe that the continued partnering of discovery-based science and translational studies will lead to novel therapeutic avenues while continuing to advance our understanding of the basic cellular activities that contribute to many human cancers.

Publications

View a list of publications by researchers at the McClatchey Laboratory

Selected Publications

Chiasson-MacKenzie C, Vitte J, Liu CH, Wright EA, Flynn EA, Stott SL, Giovannini M and McClatchey AI. Cellular mechanisms of heterogeneity in NF2-mutant schwannoma. Nat Comm 14(1):1559, 2023 March 21.

Chiasson-MacKenzie C, Morris ZS, Liu CH, Bradford WB, Koorman T, McClatchey AI. Merlin/ERM proteins regulate growth factor-induced macropinocytosis and receptor recycling by organizing the plasma membrane:cytoskeleton interface. Genes Dev. 32(17-18): 1201-14, 2018 Sep 1.

Benhamouche-Trouillet S, O’Loughlin E, Liu CH, Polachek W, Fitamant J, McKee M, El-Bardeesy N, Chen CS, McClatchey AI. Proliferation-independent role of NF2/Merlin in limiting biliary morpho- genesis. Development 145(9), 2018 April 30.

Chiasson-MacKenzie C, Morris ZS, Baca 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 Oct 26;211(2):391-405.

Hebert AM, DuBoff B, Casaletto JB, Gladden AB, McClatchey AI. Merlin/ERM proteins establish cortical asymmetry and centrosome position. Genes Dev. 2012 Dec 15;26(24):2709-23.

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 Aug 15;24(16):1718-30.

*denotes equal contribution

Our Researchers

Andrea I. McClatchey, PhD

Group Members

• Christine Chiasson-MacKenzie, PhD
• Evan O’Loughlin, PhD
• Emily A. Wright
• Youwen Zhang, PhD