Alissa Weaver, M.D., Ph.D.
Associate Professor of Cancer Biology, Pathology
Vanderbilt University Medical Center
2220 Pierce Avenue
448 Preston Research Building
Nashville, TN 37232-6840
cancer invasion, membrane trafficking, cytoskeleton, systems biology, secreted exosomes, extracellular RNA
Cancer metastasis--the spread of cancer cells to distant organs--is what kills the majority of cancer patients. In order for cells to metastasize, they must acquire an invasive and motile phenotype, degrading and moving through tissue barriers. In addition, they must be able to survive and grow at distant sites in the body. The Weaver laboratory studies all aspects of this process. We are particularly focused on how secretion of small extracellular vesicles called exosomes from cells promotes aggressive, invasive behavior and facilitates tumor growth and metastasis. Specific projects include: 1) Induction of invasive protrusion formation and exosome secretion by deregulated signaling; 2) The role of exosome secretion in tumor progression; and 3) Trafficking of RNAs in cancer exosomes.
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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- Benesh, EC, Miller, PM, Pfaltzgraff, ER, Grega-Larson, NE, Hager, HA, Sung, BH, Qu, X, Baldwin, HS, Weaver, AM, Bader, DM Bves and NDRG4 regulate directional epicardial cell migration through autocrine extracellular matrix deposition. Mol Biol Cell, 24(22), 3496-510, 2013.
- Hoshino, D, Kirkbride, KC, Costello, K, Clark, ES, Sinha, S, Grega-Larson, N, Tyska, MJ, Weaver, AM Exosome secretion is enhanced by invadopodia and drives invasive behavior. Cell Rep, 5(5), 1159-68, 2013.
- Hoshino, D, Branch, KM, Weaver, AM Signaling inputs to invadopodia and podosomes. J Cell Sci, 126(Pt 14), 2979-89, 2013.
- Weaver, AM, Page, JM, Guelcher, SA, Parekh, A Synthetic and tissue-derived models for studying rigidity effects on invadopodia activity. Methods Mol Biol, 1046171-89, 2013.
- Bryce, NS, Reynolds, AB, Koleske, AJ, Weaver, AM WAVE2 regulates epithelial morphology and cadherin isoform switching through regulation of Twist and Abl. PLoS One, 8(5), e64533, 2013.
- Branch, KM, Hoshino, D, Weaver, AM Adhesion rings surround invadopodia and promote maturation. Biol Open, 1(8), 711-22, 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.