Center for Matrix Biology - Vanderbilt University and Medical Center

Alissa M. Weaver, M.D., Ph.D.
Associate Professor in the Department of Cancer Biology

	Office Address:	771 PRB
	Mailing Address:	771 PRB Nashville, TN 37232
	Lab address:	748 PRB
	Phone:	615-936-3529
		email \| website

Secondary appointment in the Pathology department.

Research Summary

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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Research Keywords

Biochemistry, Kinase, Malignancy, Membrane, Molecular medicine, Signal transduction, Tyrosine phosphorylation,

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Associated initiative(s):

Fibrosis

Tumor Microenvironment

Career opportunities:
Postdoctoral Position Available

Selected Publications

» 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 2009. 28:431-44

» Potdar, AA, Lu, J, Jeon, J, Weaver, AM, Cummings, PT Bimodal analysis of mammary epithelial cell migration in two dimensions Ann Biomed Eng 2009. 37:230-45

» Weaver, AM Invadopodia Curr Biol 2008. 18:R362-4

» 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 2008. 283:15912-20

» Weaver, AM Cortactin in tumor invasiveness Cancer Lett 2008. 265:157-66

» Clark, ES, Weaver, AM A new role for cortactin in invadopodia: Regulation of protease secretion Eur J Cell Biol 2008. :

» Alexander, NR, Branch, KM, Parekh, A, Clark, ES, Iwueke, IC, Guelcher, SA, Weaver, AM Extracellular matrix rigidity promotes invadopodia activity Curr Biol 2008. 18:1295-9

» 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 2007. 67:4227-35

» Anderson, AR, Weaver, AM, Cummings, PT, Quaranta, V Tumor morphology and phenotypic evolution driven by selective pressure from the microenvironment Cell 2006. 127:905-15

» Weaver, AM Invadopodia: specialized cell structures for cancer invasion Clin Exp Metastasis 2006. 23:97-105

» Weaver, AM Cytoskeletal interactions with the outside world Dev Cell 2005. 9:35-8

» Quaranta, V, Weaver, AM, Cummings, PT, Anderson, AR Mathematical modeling of cancer: the future of prognosis and treatment Clin Chim Acta 2005. 357:173-9

» Bryce, NS, Clark, ES, Leysath, JL, Currie, JD, Webb, DJ, Weaver, AM Cortactin promotes cell motility by enhancing lamellipodial persistence Curr Biol 2005. 15:1276-85

» Br?!bek, J, Constancio, SS, Shin, NY, Pozzi, A, Weaver, AM, Hanks, SK CAS promotes invasiveness of Src-transformed cells Oncogene 2004. 23:7406-15

» 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 2003. 13:384-93

» Weaver, AM, Young, ME, Lee, WL, Cooper, JA Integration of signals to the Arp2/3 complex Curr Opin Cell Biol 2003. 15:23-30

» Weaver, AM, Heuser, JE, Karginov, AV, Lee, WL, Parsons, JT, Cooper, JA Interaction of cortactin and N-WASp with Arp2/3 complex Curr Biol 2002. 12:1270-8

» Cooper, JA, Wear, MA, Weaver, AM Arp2/3 complex: advances on the inner workings of a molecular machine Cell 2001. 107:703-5

» 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 2001. 11:370-4

» 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 2000. 151:29-40

» 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 1999. 9:183-90

» 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 1998. 21:85-94

» 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 1997. 47:485-487

» 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 1997. 272:14372-9

» 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 1997. 38:1841-50

» 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 1996. 320 ( Pt 2):551-5

» 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 1996. 271:24894-900

» 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 1995. 234:714-22

» 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 1995. 270:30741-8

» 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 1994. 11:432-6

» 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 1993. 218:428-41; discussion 441-3