Alissa M. Weaver, Ph.D., M.D.

Professor

alissa.weaver@vanderbilt.edu

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Faculty Appointments
Professor of Cancer Biology Professor of Pathology, Microbiology and ImmunologyProfessor of Cell & Developmental Biology
Education
M.D., Medicine, University of Virginia, Charlottesville, VirginiaPh.D., Biochemistry, University of Virginia, Charlottesville, VirginiaB.S., Biology, Stanford University, Stanford, CaliforniaB.A., Political Science , Stanford University, Stanford, California
Office Address
771 PRB
23rd Ave S @ Pierce
Nashville, NC 37232
Research Description
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.


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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
cancer invasion, membrane trafficking, cytoskeleton, systems biology, secreted exosomes, extracellular RNA
Publications
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 [print-electronic]. 2013 Dec 12/12/2013; 5(5): 1159-68. PMID: 24290760, PMCID: PMC3873329, PII: S2211-1247(13)00652-9, DOI: 10.1016/j.celrep.2013.10.050, ISSN: 2211-1247.

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 [print-electronic]. 2013 Nov; 24(22): 3496-510. PMID: 24048452, PMCID: PMC3826988, PII: mbc.E12-07-0539, DOI: 10.1091/mbc.E12-07-0539, ISSN: 1939-4586.

Hoshino D, Branch KM, Weaver AM. Signaling inputs to invadopodia and podosomes. J. Cell. Sci [print-electronic]. 2013 Jul 7/15/2013; 126(Pt 14): 2979-89. PMID: 23843616, PMCID: PMC3711196, PII: jcs.079475, DOI: 10.1242/jcs.079475, ISSN: 1477-9137.

Weaver AM, Page JM, Guelcher SA, Parekh A. Synthetic and tissue-derived models for studying rigidity effects on invadopodia activity. Methods Mol. Biol. 2013; 1046: 171-89. PMID: 23868588, DOI: 10.1007/978-1-62703-538-5_10, ISSN: 1940-6029.

Bryce NS, Reynolds AB, Koleske AJ, Weaver AM. WAVE2 regulates epithelial morphology and cadherin isoform switching through regulation of Twist and Abl. PLoS ONE [electronic-print]. 2013; 8(5): e64533. PMID: 23691243, PMCID: PMC3654908, PII: PONE-D-11-07007, DOI: 10.1371/journal.pone.0064533, ISSN: 1932-6203.

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) [print-electronic]. 2012 Sep; 69(9): 625-43. PMID: 22991200, PMCID: PMC3746372, DOI: 10.1002/cm.21051, ISSN: 1949-3592.

Branch KM, Hoshino D, Weaver AM. Adhesion rings surround invadopodia and promote maturation. Biol Open [print-electronic]. 2012 Aug 8/15/2012; 1(8): 711-22. PMID: 23213464, PMCID: PMC3507228, PII: BIO20121867, DOI: 10.1242/bio.20121867, ISSN: 2046-6390.

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. 2012; ((11 September 2012)): ra66.

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. 2012; 8((4)): e1002479.

Sung BH, Zhu X, Kaverina I, Weaver AM. Cortactin controls cell motility and lamellipodial dynamics by regulating ECM secretion. Curr. Biol. 2011 Sep 9/13/2011; 21(17): 1460-9. PMID: 21856159, PMCID: PMC3175319, PII: S0960-9822(11)00843-8, DOI: 10.1016/j.cub.2011.06.065, ISSN: 1879-0445.

Kirkbride KC, Sung BH, Sinha S, Weaver AM. Cortactin: a multifunctional regulator of cellular invasiveness. Cell Adh Migr [print-electronic]. 2011 Mar; 5(2): 187-98. PMID: 21258212, PMCID: PMC3084985, PII: 14773, ISSN: 1933-6926.

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. 2011 Feb 2/2/2011; 100(3): 573-82. PMID: 21281571, PMCID: PMC3030182, PII: S0006-3495(11)00010-5, DOI: 10.1016/j.bpj.2010.12.3733, ISSN: 1542-0086.

Sung, B.H. and A.M. Weaver. Cortactin regulation of lysosomal secretion drives fibronectin deposition and cell motility [editorial]. Bioarchitecture. 2011; 1: 257-60.

Liu S, Yamashita H, Weidow B, Weaver AM, Quaranta V. Laminin-332-beta1 integrin interactions negatively regulate invadopodia. J. Cell. Physiol. 2010 Apr; 223(1): 134-42. PMID: 20039268, PMCID: PMC3150482, DOI: 10.1002/jcp.22018, ISSN: 1097-4652.

Potdar AA, Jeon J, Weaver AM, Quaranta V, Cummings PT. Human mammary epithelial cells exhibit a bimodal correlated random walk pattern. PLoS ONE. 2010; 5(3): e9636. PMID: 20224792, PMCID: PMC2835765, DOI: 10.1371/journal.pone.0009636, ISSN: 1932-6203.

Parekh A, Weaver AM. Regulation of cancer invasiveness by the physical extracellular matrix environment. Cell Adh Migr [print-electronic]. 2009 Jul; 3(3): 288-92. PMID: 19458499, PMCID: PMC2712813, PII: 8888, ISSN: 1933-6926.

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 [print-electronic]. 2009 Jan 1/22/2009; 28(3): 431-44. PMID: 18931703, PMCID: PMC2709457, PII: onc2008389, DOI: 10.1038/onc.2008.389, ISSN: 1476-5594.

Potdar AA, Lu J, Jeon J, Weaver AM, Cummings PT. Bimodal analysis of mammary epithelial cell migration in two dimensions. Ann Biomed Eng [print-electronic]. 2009 Jan; 37(1): 230-45. PMID: 18982450, PMCID: PMC3586332, DOI: 10.1007/s10439-008-9592-y, ISSN: 1573-9686.

Weaver AM. Regulation of cancer invasion by reactive oxygen species and Tks family scaffold proteins. Sci Signal. 2009; 2(88): pe56. PMID: 19755707, PMCID: PMC2893140, PII: 2/88/pe56, DOI: 10.1126/scisignal.288pe56, ISSN: 1937-9145.

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. 2008 Oct 10/1/2008; 133(1): 79-100. PMID: 20351797, PMCID: PMC2846375, DOI: 10.1007/s10955-008-9600-5, ISSN: 0022-4715.

Alexander NR, Branch KM, Parekh A, Clark ES, Iwueke IC, Guelcher SA, Weaver AM. Extracellular matrix rigidity promotes invadopodia activity. Curr. Biol [print-electronic]. 2008 Sep 9/9/2008; 18(17): 1295-9. PMID: 18718759, PMCID: PMC2555969, PII: S0960-9822(08)01035-X, DOI: 10.1016/j.cub.2008.07.090, ISSN: 0960-9822.

Clark ES, Weaver AM. A new role for cortactin in invadopodia: regulation of protease secretion. Eur. J. Cell Biol [print-electronic]. 2008 Sep; 87(8-9): 581-90. PMID: 18342393, PMCID: PMC2566933, PII: S0171-9335(08)00024-1, DOI: 10.1016/j.ejcb.2008.01.008, ISSN: 0171-9335.

Weaver AM. Cortactin in tumor invasiveness. Cancer Lett [print-electronic]. 2008 Jul 7/8/2008; 265(2): 157-66. PMID: 18406052, PMCID: PMC2460566, PII: S0304-3835(08)00158-4, DOI: 10.1016/j.canlet.2008.02.066, ISSN: 0304-3835.

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 [print-electronic]. 2008 Jun 6/6/2008; 283(23): 15912-20. PMID: 18430734, PMCID: PMC2414292, PII: M801555200, DOI: 10.1074/jbc.M801555200, ISSN: 0021-9258.

Weaver AM. Invadopodia. Curr. Biol. 2008 May 5/6/2008; 18(9): R362-4. PMID: 18460310, PII: S0960-9822(08)00174-7, DOI: 10.1016/j.cub.2008.02.028, ISSN: 0960-9822.

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 May 5/1/2007; 67(9): 4227-35. PMID: 17483334, PII: 67/9/4227, DOI: 10.1158/0008-5472.CAN-06-3928, ISSN: 0008-5472.

Anderson AR, Weaver AM, Cummings PT, Quaranta V. Tumor morphology and phenotypic evolution driven by selective pressure from the microenvironment. Cell. 2006 Dec 12/1/2006; 127(5): 905-15. PMID: 17129778, PII: S0092-8674(06)01348-1, DOI: 10.1016/j.cell.2006.09.042, ISSN: 0092-8674.

Weaver AM. Invadopodia: specialized cell structures for cancer invasion. Clin. Exp. Metastasis [print-electronic]. 2006; 23(2): 97-105. PMID: 16830222, DOI: 10.1007/s10585-006-9014-1, ISSN: 0262-0898.

Bryce NS, Clark ES, Leysath JL, Currie JD, Webb DJ, Weaver AM. Cortactin promotes cell motility by enhancing lamellipodial persistence. Curr. Biol. 2005 Jul 7/26/2005; 15(14): 1276-85. PMID: 16051170, PII: S0960-9822(05)00678-0, DOI: 10.1016/j.cub.2005.06.043, ISSN: 0960-9822.

Quaranta V, Weaver AM, Cummings PT, Anderson AR. Mathematical modeling of cancer: the future of prognosis and treatment. Clin. Chim. Acta. 2005 Jul 7/24/2005; 357(2): 173-9. PMID: 15907826, PII: S0009-8981(05)00194-4, DOI: 10.1016/j.cccn.2005.03.023, ISSN: 0009-8981.

Weaver AM. Cytoskeletal interactions with the outside world. Dev. Cell. 2005 Jul; 9(1): 35-8. PMID: 16038069, ISSN: 1534-5807.

Brábek J, Constancio SS, Shin NY, Pozzi A, Weaver AM, Hanks SK. CAS promotes invasiveness of Src-transformed cells. Oncogene. 2004 Sep 9/23/2004; 23(44): 7406-15. PMID: 15273716, PII: 1207965, DOI: 10.1038/sj.onc.1207965, ISSN: 0950-9232.

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 Mar 3/4/2003; 13(5): 384-93. PMID: 12620186, PII: S0960982203001076, ISSN: 0960-9822.

Weaver AM, Young ME, Lee WL, Cooper JA. Integration of signals to the Arp2/3 complex. Curr. Opin. Cell Biol. 2003 Feb; 15(1): 23-30. PMID: 12517700, PII: S0955067402000157, ISSN: 0955-0674.

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 Aug 8/6/2002; 12(15): 1270-8. PMID: 12176354, PII: S0960982202010357, ISSN: 0960-9822.

Cooper JA, Wear MA, Weaver AM. Arp2/3 complex: advances on the inner workings of a molecular machine. Cell. 2001 Dec 12/14/2001; 107(6): 703-5. PMID: 11747805, PII: S0092-8674(01)00605-5, ISSN: 0092-8674.

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 Mar 3/6/2001; 11(5): 370-4. PMID: 11267876, PII: S0960-9822(01)00098-7, ISSN: 0960-9822.

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 Oct 10/2/2000; 151(1): 29-40. PMID: 11018051, PMCID: PMC2189811, ISSN: 0021-9525.

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 Apr; 9(2): 183-90. PMID: 10355824, ISSN: 1087-2906.

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 Mar; 21(2): 85-94. PMID: 9551359, ISSN: 1524-9557.

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 Sep; 38(9): 1841-50. PMID: 9323593, ISSN: 0022-2275.

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 May 5/30/1997; 272(22): 14372-9. PMID: 9162074, ISSN: 0021-9258.

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: 485-7.

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 Dec 12/1/1996; 320 ( Pt 2): 551-5. PMID: 8973565, PMCID: PMC1217964, ISSN: 0264-6021.

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 Oct 10/4/1996; 271(40): 24894-900. PMID: 8798766, ISSN: 0021-9258.

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 Dec 12/22/1995; 270(51): 30741-8. PMID: 8530514, ISSN: 0021-9258.

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 Dec 12/15/1995; 234(3): 714-22. PMID: 8575427, ISSN: 0014-2956.

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 Oct; 11(5): 432-6. PMID: 7696848, ISSN: 0282-0080.

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 Oct; 218(4): 428-41; discussion 441. PMID: 8215635, PMCID: PMC1242995, ISSN: 0003-4932.