Amy H. Bouton
- ScB, Brown University
- PhD, University of Virginia
- Postdoc, University of Virginia
- Professor, Microbiology, Immunology, and Cancer Biology
- Phone: 434-924-2513
- Email: firstname.lastname@example.org
Signaling Pathways that Regulate Tumor Growth, Metastasis, and Response to Anticancer Agents; Adhesion Signaling In Macrophages; Bacteria-Host Cell Interactions
The survival of organisms ranging from simple bacteria to complex metazoans relies on the ability of individual cells to sample the environment and respond appropriately. Understanding the molecular pathways involved in these responses is of fundamental importance for many areas of biomedical science including cancer biology and microbial pathogenesis, both of which are major research foci of our lab. A short description of our work in each of these areas is presented below. One of the major research areas in our lab focuses on determining molecular mechanisms by which breast cancer cells become resistant to the growth-inhibitory effects of a class of compounds called antiestrogens (competitive inhibitors of the estrogen receptor). This is a significant problem in breast cancer treatment, since approximately 50% of breast tumors never respond to antiestrogen therapy, and the majority of tumors that initially respond acquire resistance to these drugs over time. We have been investigating the biological activities of two proteins, Cas and BCAR3, which have been shown to confer resistance of breast cancer cells in culture to antiestrogens such as tamoxifen. Interestingly, human breast tumors that overexpress Cas are significantly less likely to respond to first-line tamoxifen therapy, and the prognosis of patients with these tumors is poor. We hypothesize that one of the effects of high Cas and BCAR3 expression is activation of signaling pathways that allow breast cancer cells that are usually dependent on estrogens for growth to proliferate in the absence of estrogens. We are currently testing aspects of this hypothesis using both tissue culture and mouse models of breast cancer with the goal of 1) better predicting whether a particular tumor is likely to fail antiestrogen therapy so that other treatment approaches can be initiated more quickly, and 2) rendering previously resistant tumors sensitive to tamoxifen treatment by blocking Cas- or BCAR3-specific functions.
Our research program also studies adhesion signaling in macrophages. As a key component of the innate immune system, macrophages play a central role during tissue remodeling and following injury or infection. Because of their broad functions and heterogeneous character, these cells are extremely responsive to environmental cues that signal the need for differentiation and maturation, activation, migration and invasion, and/or phagocytosis. Two protein tyrosine kinases, focal adhesion kinase (FAK) and its close relative Pyk2, function as regulators of many of these biological processes. Using both mouse models and primary bone marrow macrophages, we have been investigating how FAK and Pyk2 regulate macrophage adhesion, migration, infiltration into sites of inflammation, and phagocytosis of the bacterial pathogen Yersinia pseudotuberculosis.
In addition to our work on basic macrophage cell biology and innate immunity, we have been studying how FAK expression in macrophages contributes to breast and melanoma tumor growth and metastasis. In recent years, it has become clear that tumor progression and metastasis are not only governed by the genetic properties of tumor cells, but also by interactions between the tumor cells and a large assortment of "host" cells that make up the "tumor microenvironment." Tumor-associated macrophages (TAMs), which are an important immunological component of the tumor microenvironment, have been shown to promote the growth and metastatic spread of breast tumor cells. However, the mechanisms through which TAMs communicate with tumor cells to promote tumor growth and metastasis are not clear. We have been testing the hypothesis that FAK may contribute to the tumor-promoting activity of TAMs with the use of a myeloid-specific conditional FAK knockout mouse, in which FAK is genetically deleted from cells of the myeloid lineage (including macrophages). These studies address a pressing need in the field of tumor biology to understand the molecular and cellular mechanisms that underlie the communication between macrophages that function within the tumor microenvironment and the tumor cells themselves. They also provide the experimental underpinning for designing therapeutic strategies that combine drugs that target tumor cells with drugs that target the supporting cells of the microenvironment that contribute to tumor growth and metastasis. In fact, small molecule inhibitors of FAK have recently been identified that exhibit significant anti-tumor effects in preclinical models and Phase I clinical trials. The mouse model that we are developing will allow us to gain a better understanding of how these drugs might be used in combination with other cancer therapeutics to control tumor growth and metastasis.
- Gutknecht M, Bouton A. Functional significance of mononuclear phagocyte populations generated through adult hematopoiesis. Journal of leukocyte biology. 2014. PMID: 25225678 | PMCID: PMC4226790
- Owen K, Meyer C, Bouton A, Casanova J. Activation of focal adhesion kinase by Salmonella suppresses autophagy via an Akt/mTOR signaling pathway and promotes bacterial survival in macrophages. PLoS pathogens. 2014;10(6): e1004159. PMID: 24901456 | PMCID: PMC4047085
- Zhao Y, Kumbrink J, Lin B, Bouton A, Yang S, Toselli P, Kirsch K. Expression of a phosphorylated substrate domain of p130Cas promotes PyMT-induced c-Src-dependent murine breast cancer progression. Carcinogenesis. 2013;34(12): 2880-90. PMID: 23825155 | PMCID: PMC3845889
- Ray B, Thomas K, Huang C, Gutknecht M, Botchwey E, Bouton A. Regulation of osteoclast structure and function by FAK family kinases. Journal of leukocyte biology. 2012. PMID: 22941736 | PMCID: PMC3476245
- Owen K, Abshire M, Tilghman R, Casanova J, Bouton A. FAK regulates intestinal epithelial cell survival and proliferation during mucosal wound healing. PloS one. 2011;6(8): e23123. PMID: 21887232 | PMCID: PMC3160839
- Stokes J, Adair S, Slack-Davis J, Walters D, Tilghman R, Hershey E, Lowrey B, Thomas K, Bouton A, Hwang R, Stelow E, Parsons J, Bauer T. Inhibition of focal adhesion kinase by PF-562,271 inhibits the growth and metastasis of pancreatic cancer concomitant with altering the tumor microenvironment. Molecular cancer therapeutics. 2011;10(11): 2135-45. PMID: 21903606 | PMCID: PMC3213273
- Abshire M, Thomas K, Owen K, Bouton A. Macrophage motility requires distinct α5β1/FAK and α4β1/paxillin signaling events. Journal of leukocyte biology. 2010;89(2): 251-7. PMID: 21084629 | PMCID: PMC3024900
- Schuh N, Guerrero M, Schrecengost R, Bouton A. BCAR3 regulates Src/p130 Cas association, Src kinase activity, and breast cancer adhesion signaling. The Journal of biological chemistry. 2009;285(4): 2309-17. PMID: 19940159 | PMCID: PMC2807288
- Ta H, Thomas K, Schrecengost R, Bouton A. A novel association between p130Cas and resistance to the chemotherapeutic drug adriamycin in human breast cancer cells. Cancer research. 2008;68(21): 8796-804. PMID: 18974122 | PMCID: PMC2597570
- Owen K, Pixley F, Thomas K, Vicente-Manzanares M, Ray B, Horwitz A, Parsons J, Beggs H, Stanley E, Bouton A. Regulation of lamellipodial persistence, adhesion turnover, and motility in macrophages by focal adhesion kinase. The Journal of cell biology. 2007;179(6): 1275-87. PMID: 18070912 | PMCID: PMC2140030
- Cowell L, Graham J, Bouton A, Clarke C, O'Neill G. Tamoxifen treatment promotes phosphorylation of the adhesion molecules, p130Cas/BCAR1, FAK and Src, via an adhesion-dependent pathway. Oncogene. 2006;25(58): 7597-607. PMID: 16799644
- Riggins R, Thomas K, Ta H, Wen J, Davis R, Schuh N, Donelan S, Owen K, Gibson M, Shupnik M, Silva C, Parsons S, Clarke R, Bouton A. Physical and functional interactions between Cas and c-Src induce tamoxifen resistance of breast cancer cells through pathways involving epidermal growth factor receptor and signal transducer and activator of transcription 5b. Cancer research. 2006;66(14): 7007-15. PMID: 16849545