Andrea Page-McCaw, Ph.D.
Vanderbilt University Medical Center
465 21st Avenue South
MRBIII, rm 4120B
Nashville, TN 37232-8240
Matrix metalloproteinases (MMPs) can cleave components of the extracellular matrix. They are upregulated in most tumors and are believed to facilitate tumor growth and invasion. Accordingly, MMP inhibitors have been the targets of several clinical trials. Yet the use of MMP inhibitors as therapeutic agents has been problematic as they have caused unacceptable side effects. These side effects highlight the importance of understanding the normal physiological and developmental roles of MMPs. My laboratory is examining the requirements for MMPs in a model organism Drosophila melaogaster. Although vertebrates have more than 20 MMP family members, Drosophila has only two (non-redundant) MMPs; this organism is also highly amenable to developmental and physiological studies at the genetic and cell biological level. Our studies have demonstrated that MMPs are absolutely required for tissue remodeling events that normally occur during growth and during the transition from juvenile to adult forms.
My laboratory has an additional focus on wound healing. Normal wound healing shares many similarities with the tumor microenvironment, and indeed tumor invasion has been compared to “wound healing gone awry.” We are examining the contributions of blood cells and epithelia to healing normal epithelial wounds. In our model system, MMPs are required in both blood and in epithelia, as animals lacking MMPs in either tissue cannot heal puncture wounds. We seek to understand the functions of MMPs in this normal physiological process to use these findings to understand the tumor microenvironment.
Matrix metalloproteinases (MMPs), tissue remodeling, wound healing, basement membrane, extracellular matrix, developmental biology, Drosophila, genetics, signaling.
During embryogenesis, animals develop complex structures, but they often have to modify their morphology to meet the demands of continuing growth or environmental challenge. This is known as tissue remodeling. Tissue remodeling is also required for animals to heal wounds, and it goes awry during cancer when tumors usurp tissue remodeling functions to promote metastasis. The matrix metalloproteinase (MMP) family of extracellular proteases is required for tissue remodeling events throughout the animal kingdom. These proteases are also upregulated in cancer and many inflammatory conditions such as arthritis. Understanding how MMPs promote tissue remodeling, both in normal and pathological circumstances, is a central question in my laboratory.
Drosophila melanogaster (the common fruitfly) has been an important model organism for understanding cell and developmental biology because of their advanced genetics and beautiful cytology. Although mammals have about 24 MMPs with overlapping substrate specificity and functional redundancy, Drosophila has only two MMPs, greatly simplifying genetic analysis of MMP function. We have found MMPs to be absolutley required for developmental tissue remodeling and epidermal wound healing in our system. We are currently investigating how basement membrane is modified and expanded in coordination with tissue growth during development.
- Stevens, LJ, Page-McCaw, A A secreted MMP is required for reepithelialization during wound healing. Mol Biol Cell, 23(6), 1068-79, 2012.
- Miller, CM, Liu, N, Page-McCaw, A, Broihier, HT Drosophila mmp2 regulates the matrix molecule faulty attraction (frac) to promote motor axon targeting in Drosophila. J Neurosci, 31(14), 5335-47, 2011.
- Glasheen, BM, Robbins, RM, Piette, C, Beitel, GJ, Page-McCaw, A A matrix metalloproteinase mediates airway remodeling in Drosophila. Dev Biol, 344(2), 772-83, 2010.
- Glasheen, BM, Kabra, AT, Page-McCaw, A Distinct functions for the catalytic and hemopexin domains of a Drosophila matrix metalloproteinase. Proc Natl Acad Sci U S A, 106(8), 2659-64, 2009.
- Miller, CM, Page-McCaw, A, Broihier, HT Matrix metalloproteinases promote motor axon fasciculation in the Drosophila embryo. Development, 135(1), 95-109, 2008.
- Page-McCaw, A Remodeling the model organism: matrix metalloproteinase functions in invertebrates. Semin Cell Dev Biol, 19(1), 14-23, 2008.
- Page-McCaw, A, Ewald, AJ, Werb, Z Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol, 8(3), 221-33, 2007.
- Beaucher, M, Hersperger, E, Page-McCaw, A, Shearn, A Metastatic ability of Drosophila tumors depends on MMP activity. Dev Biol, 303(2), 625-34, 2007.
- Zhang, S, Dailey, GM, Kwan, E, Glasheen, BM, Sroga, GE, Page-McCaw, A An MMP liberates the Ninjurin A ectodomain to signal a loss of cell adhesion. Genes Dev, 20(14), 1899-910, 2006.
- Myllykangas, L, TyynelÃ¤, J, Page-McCaw, A, Rubin, GM, Haltia, MJ, Feany, MB Cathepsin D-deficient Drosophila recapitulate the key features of neuronal ceroid lipofuscinoses. Neurobiol Dis, 19(1-2), 194-9, 2004.
- Page-McCaw, A, Serano, J, Sante, JM, Rubin, GM Drosophila matrix metalloproteinases are required for tissue remodeling, but not embryonic development. Dev Cell, 4(1), 95-106, 2003.