Katherine Swenson-Fields

Anatomy and Cell Biology – Research Associate Professor
Kidney Institute – Member
Anatomy and Cell Biology

Ph.D.: University of Washington, Seattle, WA
Postdoctoral training: Department of Anatomy and Cellular Biology, Harvard Medical School

Publications: Click here

Research Focus

The long standing focus of my research has been centered on signaling pathways that regulate the processes of cell cycle progression and cell migration. In collaboration with the laboratory of Dr. Tim Fields, we have recently initiated studies of the Wnt signaling pathways in melanoma. Wnt is a secreted extracellular protein that acts to influence decisions of multipotent precursor cells as they become committed to specialized fates. Wnt signaling influences cell proliferation, differentiation, migration and morphology, and inappropriate activation of Wnt-stimulated pathways can lead to cancer. Most cancers initiated or maintained by inappropriate Wnt signaling are due to over stimulation of the canonical Wnt pathway resulting in the stabilization and nuclear accumulation of ß-catenin, which acts as a transcriptional co-activator to induce Wnt target genes. However, most aggressive melanomas are best characterized not by the presence of elevated canonical Wnt signaling, but by the overexpression of a noncanonical Wnt, Wnt5a. Wnt5a signals in the noncanonical pathway by binding the Ror2 tyrosine kinase receptor to initiate a number of pathways that can lead to the activation of Jnk and/or an increase in intracellular Ca++. By mechanisms that are not well understood, the presence of Wnt5a normally acts to inhibit signaling of canonical Wnt/ß-catenin pathways and thus can exhibit tumor suppressor activity in many carcinomas, presumably by inhibiting proliferative effects of canonical Wnts. Wnt5a also has a role in cell migration and is required during development for polarized movement of multiple cell types. By signaling through the Ror2 receptor and Jnk activation, Wnt5a stimulates polarized lamellipodia formation and reorganization of the microtubule cytoskeleton that is required for directed cell migration. In melanoma cells, Wnt5a is believed to promote aggressive tumor behavior rather than act as a tumor suppressor. The overexpression of Wnt5a has been found to be the best marker gene for distinguishing highly aggressive melanomas from those that are less aggressive. Transfection of Wnt5a into less aggressive melanoma cell increases their invasive potential and knockdown of Wnt5a in more aggressive melanoma cells inhibits motility.

The long standing focus of my research has been centered on signaling pathways that regulate the processes of cell cycle progression and cell migration. In collaboration with the laboratory of Dr. Tim Fields (web page in preparation), we have recently initiated studies of the Wnt signaling pathways in melanoma. Wnt is a secreted extracellular protein that acts to influence decisions of multipotent precursor cells as they become committed to specialized fates. Wnt signaling influences cell proliferation, differentiation, migration and morphology, and inappropriate activation of Wnt-stimulated pathways can lead to cancer. Most cancers initiated or maintained by inappropriate Wnt signaling are due to over stimulation of the canonical Wnt pathway resulting in the stabilization and nuclear accumulation of ß-catenin, which acts as a transcriptional co-activator to induce Wnt target genes. However, most aggressive melanomas are best characterized not by the presence of elevated canonical Wnt signaling, but by the overexpression of a noncanonical Wnt, Wnt5a.

Wnt5a signals in the noncanonical pathway by binding the Ror2 tyrosine kinase receptor to initiate a number of pathways that can lead to the activation of Jnk and/or an increase in intracellular Ca++. By mechanisms that are not well understood, the presence of Wnt5a normally acts to inhibit signaling of canonical Wnt/ß-catenin pathways and thus can exhibit tumor suppressor activity in many carcinomas, presumably by inhibiting proliferative effects of canonical Wnts. Wnt5a also has a role in cell migration and is required during development for polarized movement of multiple cell types. By signaling through the Ror2 receptor and Jnk activation, Wnt5a stimulates polarized lamellipodia formation and reorganization of the microtubule cytoskeleton that is required for directed cell migration.

In melanoma cells, Wnt5a is believed to promote aggressive tumor behavior rather than act as a tumor suppressor. The overexpression of Wnt5a has been found to be the best marker gene for distinguishing highly aggressive melanomas from those that are less aggressive. Transfection of Wnt5a into less aggressive melanoma cell increases their invasive potential and knockdown of Wnt5a in more aggressive melanoma cells inhibits motility. Our questions are: Why does Wnt5a promote aggressive tumor behavior in melanoma cells rather than act as a tumor suppressor as it appears to do in breast and colon cancer? What are the signaling components required for Wnt5a-stimulated cell polarization? Can the tumorigenic/metastatic potential of melanoma be abrograted by blocking Wnt5a signaling? To study these question, we are delineating the effects of Wnt5a on canonical signaling in normal melanocytes and melanomas. We also are focused on determining whether these pathways affecting transcriptional output crosstalk with those resulting in the cytoarchitectural changes required for cell migration. In addition, efforts are underway to produce extracellular inhibitors of Wnt5a signaling with the goal of producing agents that can be used therapeutically to intervene with melanoma progression in vivo.