Research Centers
McClatchey
Program affiliations
Andrea I. McClatchey, PhD
Associate Professor of Pathology
Harvard Medical School
Assistant Geneticist
Center for Cancer Research
Research Summary
Understanding Morphogenesis and Tumorigenesis
The overarching goal of our laboratory is to understand how cell membrane organization is utilized during morphogenesis and deregulated in tumorigenesis. This stems from a longstanding interest in delineating the molecular pathogenesis of familial neurofibromatosis type 2 (NF2). The NF2-encoded tumor suppressor, Merlin, is related to the ERM proteins that link membrane proteins to the cortical cytoskeleton, eliciting the question of how proliferation can be inhibited from the membrane:cytoskeleton interface. We originally generated an Nf2-mutant mouse strain and uncovered broad consequences of Nf2-deficiency in development and metastatic tumorigenesis.
Our early studies established the now widely accepted model of Merlin regulation wherein activation of the small GTPase Rac yields phosphorylation and inactivation of Merlin. Subsequent studies of primary Nf2-/- cells revealed that Merlin normally mediates contact-dependent inhibition of proliferation by coordinating the stabilization of cell:cell contacts with silencing of Epidermal Growth Factor Receptor (EGFR) signaling, linking Merlin to a well-known oncogene. Importantly, pharmacologic EGFR inhibitors, such as Iressa® (gefitinib) and Tarceva® (erlotinib) block the overproliferation of several types of Nf2-/- cells, suggesting therapeutic strategies for NF2.
Our mechanistic studies revealed that Merlin associates with and inhibits EGFR signaling and internalization upon cell:cell contact at least in part via an adapter protein called NHE-RF1. This complemented our discovery that Ezrin is essential for apical membrane integrity and junctional remodeling during epithelial morphogenesis and for apical localization of NHE-RF1. Thus Merlin/ERMs may organize distinct membrane domains by spatiotemporally controlling NHE-RF-associated receptors. Our work highlights the heterogeneous, context-dependent distribution/signaling of membrane receptors and has important implications for delineating their C roles in tumorigenesis. Ongoing studies utilize single particle tracking to study the effect of Merlin on the movement of individual EGFR molecules.
Several lines of evidence indicate a functional relationship between Merlin and the ERM proteins. To study this relationship we generated a conditional mutation in the mouse Ezrin gene. Through the study of these mice, we have identified a critical role for Ezrin in intestinal villus morphogenesis and in the assembly of the apical surface of polarizing epithelial cells. We have also identified a previously unrecognized morphogenetic step in intestinal homeostasis in the adult intestine by removing Ezrin function specifically in the adult intestine. Current studies are aimed at better defining the mechanism whereby Ezrin controls apical membrane integrity and receptor function, using our versatile conditional allele to identify other cell types that require Ezrin function and delineating the relationship between Merlin and Ezrin in tumor development and metastasis.
More recently, we have generated an exciting mouse model of stem cell-derived liver cancer. Extending our previous observation that Nf2+/- mice spontaneously develop both liver cancer, we conditionally deleted Nf2 in the developing mouse liver. Within a few weeks, these mice exhibit a dramatic expansion of undifferentiated cells that resemble bipotential liver progenitors. Remarkably, these mice invariably go on to develop both metastatic hepatocellular carcinoma and cholangiocarcinoma. Using our studies of other types of Nf2-/- cells, as a guide, we have investigated the molecular basis for hyperproliferation of these Nf2-/- liver precurser cells, and found that they fail to undergo contact-dependent inhibition of proliferation, to form stable adherens junctions or to downregulate EGFR signaling upon cell contact; pharmacologic inhibition of EGFR activity reverts these phenotypes. We have initiated a pilot preclinical study of the ability of Tarceva® (erlotinib) to prevent oval cell hyperproliferation or to affect stabilization or regression of lesions in these mice.
Preliminary studies suggest that Merlin may play a similar role in controlling the proliferation of progenitor cells in other tissues. Our most advanced studies are in the skin, where we discovered that loss of Nf2 yields overproliferation of cells in the basal layer of the epidermis. Importantly, we also found that Nf2-deficiency causes aberrant asymmetric cell division and altered distribution of polarity complexes. Ongoing studies aim to delineate the role of Merlin in linking cell polarity and proliferation in this model. Initial studies suggest similar consequences of Nf2 loss in the intestinal, renal and mammary epithelia.
Finally, we have identified and begun to study the mammalian homologue of the Drosophila tumor suppressor, Expanded, which is related to Merlin and the ERM proteins and is a physical and genetic interactor of Merlin in the fly. Recent studies in the fly have linked Expanded (and perhaps Merlin) to the Hippo/Warts tumor suppressor pathway, generating intense interest in the nature of this relationship and in the analogous mammalian pathway. Indeed, our initial studies suggest that mouse Expanded also plays a role in cell:cell communication; the generation of a conditional Ex-mutant allele in the mouse genome is well underway.
Collectively, our studies continue to utilize the mouse as a model system for delineating the molecular functions of Merlin and the ERM proteins (and Expanded), their roles in organizing membranes and receptor signaling during tissue morphogenesis and the consequences of their deregulation in tumor initiation and progression. A key goal will be to continue to apply our molecular studies to the development and preclinical testing of therapeutic strategies for NF2. These studies will also serve as a paradigm for understanding the role of the membrane:cytoskeleton interface in cancer development and metastasis.
Andrea I. McClatchey, PhD
Principal Investigator
Group Members
- Samira Benhamouche, PhD
- Jessica Casaletto
- Wai Fong Annie Chan
- Marcello Curto
- Andrew Gladden
- Alan Hebert
- Zachary Morris
- Ichiko Saotome
McClatchey Laboratory
Bldg 149, 13th Street7th Floor
Charlestown, MA 02129
Phone: 617-726-5648
Email: mcclatch@helix.mgh.harvard.edu
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