Alissa Weaver, M.D. , Ph.D.
Associate Professor of Cancer Biology, Pathology
Vanderbilt University Medical Center
448 Preston Research Building, 2220 Pierce Avenue
Nashville, TN 37232-6840
Dynamic actin assembly for cell motility and cancer metastasis.
Cell motility is important for a number of physiologic and pathologic processes, including wound healing, immune system function, axon guidance, and cancer cell metastasis. In order for a cell to move, it must rapidly rearrange its actin cytoskeleton to produce the required cell shape changes and to generate force. Among the various forms of actin structures in cells, the most dynamic (assembled and disassembled in a matter of seconds) are the branched actin filament networks nucleated by the Arp2/3 protein complex. Arp2/3 complex is essential for plasma membrane protrusion at the leading edge of migrating cells and is also important in such processes as endocytosis, cell-cell junction formation, and the formation of subcellular structures used for cancer cell invasion (invadopodia).
Activation of Arp2/3 complex in cells occurs in response to a variety of signals, including from growth factors, src family kinases, and rho GTPases. Cellular activators include members of the Wiskott-Aldrich Syndrome family of proteins (WASps) and cortactin, a src kinase substrate that is overexpressed in a number of epithelial cancers. A major goal of the laboratory is to understand how Arp2/3-activators and associated signaling molecules contribute to cell motility and cancer invasion. We use a variety of techniques including siRNA, live-cell imaging, and biochemistry. Specific projects include: 1) cortactin and WASp family function in lamellipodial protrusion and cell motility; 2) actin assembly in membrane trafficking and autocrine secretion; 3) role of cortactin in head and neck squamous carcinoma progression; 4) molecular regulation of invadopodia; 5) determining critical parameters for invasion of breast cancer cells in three dimensions; and 6) interdisciplinary projects focused on mathematical modeling of cancer invasion.
Figure 1: Breast cancer cell stained with rhodamine-phalloidin to reveal filamentous actin (left panel) at sites of invasion into fluorescent basement membrane (middle panel: FITC-fibronectin). Right panel: merge of images.
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- Branch, KM, Hoshino, D, and Weaver, AM "Adhesion rings surround invadopodia and promote maturation." Biology Open, 1711-722, 2012.
- Hoshino, D, Koshikawa, N, Suzuki, T, Quaranta, V, Weaver, AM, Seiki, M, and K Ichikawa "Establishment and validation of computational model for MT1-MMP dependent ECM degradation and intervention strategies.." PLoS Computational Biology, 8(4), e1002479, 2012.
- Hoshino, D, Jourquin, J, Emmons, SW, Miller, T, Goldgof, M, Costello, K, Tyson, DR, Brown, B, Lu, Y, Prasad, NK, Zhang, B, Mills, GB, Yarbrough, WG, Quaranta, V, Seiki, M, and AM Weaver "Network analysis of the focal adhesion to invadopodia transition identifies a PI3K-PKCa invasive signaling axis." Science Signaling, (11 September 2012), ra66, 2012.
- Kirkbride, KC, Hong, NH, French, CL, Clark, ES, Jerome, WG, Weaver, AM Regulation of late endosomal/lysosomal maturation and trafficking by cortactin affects Golgi morphology. Cytoskeleton (Hoboken), 69(9), 625-43, 2012.
- Sung, BH, Zhu, X, Kaverina, I, Weaver, AM Cortactin controls cell motility and lamellipodial dynamics by regulating ECM secretion. Curr Biol, 21(17), 1460-9, 2011.
- Sung, B.H. and A.M. Weaver "Cortactin regulation of lysosomal secretion drives fibronectin deposition and cell motility." Bioarchitecture, 1257-260, 2011.
- Kirkbride, KC, Sung, BH, Sinha, S, Weaver, AM Cortactin: a multifunctional regulator of cellular invasiveness. Cell Adh Migr, 5(2), 187-98, 2011.
- Parekh, A, Ruppender, NS, Branch, KM, Sewell-Loftin, MK, Lin, J, Boyer, PD, Candiello, JE, Merryman, WD, Guelcher, SA, Weaver, AM Sensing and modulation of invadopodia across a wide range of rigidities. Biophys J, 100(3), 573-82, 2011.
- Potdar, AA, Jeon, J, Weaver, AM, Quaranta, V, Cummings, PT Human mammary epithelial cells exhibit a bimodal correlated random walk pattern. PLoS One, 5(3), e9636, 2010.
- Liu, S, Yamashita, H, Weidow, B, Weaver, AM, Quaranta, V Laminin-332-beta1 integrin interactions negatively regulate invadopodia. J Cell Physiol, 223(1), 134-42, 2010.
- Clark, ES, Brown, B, Whigham, AS, Kochaishvili, A, Yarbrough, WG, Weaver, AM Aggressiveness of HNSCC tumors depends on expression levels of cortactin, a gene in the 11q13 amplicon. Oncogene, 28(3), 431-44, 2009.
- Potdar, AA, Lu, J, Jeon, J, Weaver, AM, Cummings, PT Bimodal analysis of mammary epithelial cell migration in two dimensions. Ann Biomed Eng, 37(1), 230-45, 2009.
- Weaver, AM Regulation of cancer invasion by reactive oxygen species and Tks family scaffold proteins. Sci Signal, 2(88), pe56, 2009.
- Parekh, A, Weaver, AM Regulation of cancer invasiveness by the physical extracellular matrix environment. Cell Adh Migr, 3(3), 288-92, 2009.
- Clark, ES, Weaver, AM A new role for cortactin in invadopodia: Regulation of protease secretion. Eur J Cell Biol, 2008.
- Weaver, AM Cortactin in tumor invasiveness. Cancer Lett, 265(2), 157-66, 2008.
- Alexander, NR, Branch, KM, Parekh, A, Clark, ES, Iwueke, IC, Guelcher, SA, Weaver, AM Extracellular matrix rigidity promotes invadopodia activity. Curr Biol, 18(17), 1295-9, 2008.
- Weaver, AM Invadopodia. Curr Biol, 18(9), R362-4, 2008.
- Wegner, AM, Nebhan, CA, Hu, L, Majumdar, D, Meier, KM, Weaver, AM, Webb, DJ N-wasp and the arp2/3 complex are critical regulators of actin in the development of dendritic spines and synapses. J Biol Chem, 283(23), 15912-20, 2008.
- Jeon, J, Alexander, NR, Weaver, AM, Cummings, PT Protrusion of a Virtual Model Lamellipodium by Actin Polymerization: A Coarse-grained Langevin Dynamics Model. J Stat Phys, 133(1), 79-100, 2008.
- Clark, ES, Whigham, AS, Yarbrough, WG, Weaver, AM Cortactin is an essential regulator of matrix metalloproteinase secretion and extracellular matrix degradation in invadopodia. Cancer Res, 67(9), 4227-35, 2007.
- Weaver, AM Invadopodia: specialized cell structures for cancer invasion. Clin Exp Metastasis, 23(2), 97-105, 2006.
- Anderson, AR, Weaver, AM, Cummings, PT, Quaranta, V Tumor morphology and phenotypic evolution driven by selective pressure from the microenvironment. Cell, 127(5), 905-15, 2006.
- Bryce, NS, Clark, ES, Leysath, JL, Currie, JD, Webb, DJ, Weaver, AM Cortactin promotes cell motility by enhancing lamellipodial persistence. Curr Biol, 15(14), 1276-85, 2005.
- Weaver, AM Cytoskeletal interactions with the outside world. Dev Cell, 9(1), 35-8, 2005.
- Quaranta, V, Weaver, AM, Cummings, PT, Anderson, AR Mathematical modeling of cancer: the future of prognosis and treatment. Clin Chim Acta, 357(2), 173-9, 2005.
- BrÃ¡bek, J, Constancio, SS, Shin, NY, Pozzi, A, Weaver, AM, Hanks, SK CAS promotes invasiveness of Src-transformed cells. Oncogene, 23(44), 7406-15, 2004.
- Kinley, AW, Weed, SA, Weaver, AM, Karginov, AV, Bissonette, E, Cooper, JA, Parsons, JT Cortactin interacts with WIP in regulating Arp2/3 activation and membrane protrusion. Curr Biol, 13(5), 384-93, 2003.
- Weaver, AM, Young, ME, Lee, WL, Cooper, JA Integration of signals to the Arp2/3 complex. Curr Opin Cell Biol, 15(1), 23-30, 2003.
- Weaver, AM, Heuser, JE, Karginov, AV, Lee, WL, Parsons, JT, Cooper, JA Interaction of cortactin and N-WASp with Arp2/3 complex. Curr Biol, 12(15), 1270-8, 2002.
- Cooper, JA, Wear, MA, Weaver, AM Arp2/3 complex: advances on the inner workings of a molecular machine. Cell, 107(6), 703-5, 2001.
- Weaver, AM, Karginov, AV, Kinley, AW, Weed, SA, Li, Y, Parsons, JT, Cooper, JA Cortactin promotes and stabilizes Arp2/3-induced actin filament network formation. Curr Biol, 11(5), 370-4, 2001.
- Weed, SA, Karginov, AV, Schafer, DA, Weaver, AM, Kinley, AW, Cooper, JA, Parsons, JT Cortactin localization to sites of actin assembly in lamellipodia requires interactions with F-actin and the Arp2/3 complex. J Cell Biol, 151(1), 29-40, 2000.
- Hussaini, IM, Brown, MD, Weaver, AM, Carpenter, J, Karns, LR, Vandenberg, SR, Gonias, SL Stable antisense RNA expression neutralizes the activity of low-density lipoprotein receptor-related protein and promotes urokinase accumulation in the medium of an astrocytic tumor cell line. Antisense Nucleic Acid Drug Dev, 9(2), 183-90, 1999.
- Harthun, NL, Weaver, AM, Brinckerhoff, LH, Deacon, DH, Gonias, SL, Slingluff, CL Activated alpha 2-macroglobulin reverses the immunosuppressive activity in human breast cancer cell-conditioned medium by selectively neutralizing transforming growth factor-beta in the presence of interleukin-2. J Immunother, 21(2), 85-94, 1998.
- Weaver, AM, Hussaini, IM, Mazar, A, Henkin, J, Gonias, SL Embryonic fibroblasts that are genetically deficient in low density lipoprotein receptor-related protein demonstrate increased activity of the urokinase receptor system and accelerated migration on vitronectin. J Biol Chem, 272(22), 14372-9, 1997.
- Weaver, AM, Lysiak, JJ, Gonias, SL LDL receptor family-dependent and -independent pathways for the internalization and digestion of lipoprotein lipase-associated beta-VLDL by rat vascular smooth muscle cells. J Lipid Res, 38(9), 1841-50, 1997.
- Harthun, N.L., Weaver, A.M., Deacon, D.H., Gonias, S.L., and C.L. Slingluff "Production of soluble immunosuppressive factors by human breast cancer and the neutralization of these factors by activated a2-macroglobulin." Surgical Forum, 47485-487, 1997.
- Weaver, AM, McCabe, M, Kim, I, Allietta, MM, Gonias, SL Epidermal growth factor and platelet-derived growth factor-BB induce a stable increase in the activity of low density lipoprotein receptor-related protein in vascular smooth muscle cells by altering receptor distribution and recycling. J Biol Chem, 271(40), 24894-900, 1996.
- Webb, DJ, Weaver, AM, Atkins-Brady, TL, Gonias, SL Proteinases are isoform-specific regulators of the binding of transforming growth factor beta to alpha 2-macroglobulin. Biochem J, 320 ( Pt 2)551-5, 1996.
- Webb, DJ, Hussaini, IM, Weaver, AM, Atkins, TL, Chu, CT, Pizzo, SV, Owens, GK, Gonias, SL Activated alpha 2-macroglobulin promotes mitogenesis in rat vascular smooth muscle cells by a mechanism that is independent of growth-factor-carrier activity. Eur J Biochem, 234(3), 714-22, 1995.
- Weaver, AM, Owens, GK, Gonias, SL Native and activated forms of alpha 2-macroglobulin increase expression of platelet-derived growth factor alpha-receptor in vascular smooth muscle cells. Evidence for autocrine transforming growth factor-beta activity. J Biol Chem, 270(51), 30741-8, 1995.
- McCoy, JJ, Weaver, AM, Petri, WA Use of monoclonal anti-light subunit antibodies to study the structure and function of the Entamoeba histolytica Gal/GalNAc adherence lectin. Glycoconj J, 11(5), 432-6, 1994.
- Earnhardt, RC, Kindler, DD, Weaver, AM, Cornett, G, Elahi, D, Veldhuis, JD, Hanks, JB Hyperinsulinemia after pancreatic transplantation. Prediction by a novel computer model and in vivo verification. Ann Surg, 218(4), 428-41; discussion 441-3, 1993.