National Institute on Aging, Intramural Research Program

National Institute on Aging
National Institutes of Health

Ashani Weeraratna , Ph.D., Staff Scientist
Head, Cancer Biology Unit
Laboratory of Immunology
E-mail: Weerarat@grc.nia.nih.gov

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Biography:Dr. Weeraratna is currently a Staff Scientist and Head of the Cancer Biology Unit of the Laboratory of Immunology, at the National Institute on Aging. She received her PhD in Molecular and Cellular Oncology from the George Washington University Medical Center, Dept. of Pharmacology in 1998. From 1998 to 2000, she pursued a post-doctoral fellowship at the Johns Hopkins Oncology Center, before joining the National Human Genome Research Institute as a Staff Scientist. Dr. Weeraratna joined the National Institute on Aging in 2003. Her laboratory focuses on unraveling the molecular mechanisms involved in melanoma metastasis with a particular emphasis on Wnt signaling. She is also interested in mechanisms leading to cancer cell senescence and the link between cancer and aging.

Overview - Research: The prevalence of melanoma has continued to rise over the last several decades. The statistics of recurrent melanoma indicate a dearth of effective treatments for this disease, and identifying which genes and pathways underlie the progression of melanoma may help reveal viable targets for future therapy. Our research focuses on identifying these pathways, and assessing their contribution to the invasiveness of melanoma, and the viability of effectors or intermediates of these pathways as molecular targets for improved therapy. We are also extremely interested in exploring the common features between aging and malignant cells.

Molecular Mechanisms Underlying Melanoma Metastasis: Thus far, data generated by microarray and SAGE analyses from our laboratory have highlighted the importance of G-protein mediated signaling, resulting in the activation of PKC and rises in intracellular calcium in melanoma progression. These effects can be mediated by the gene WNT5A, the over expression of which can lead to increases in melanoma cell motility and invasion. RNAi inhibition of this pathway, followed by microarray analysis, revealed that Wnt5A may make this contribution to invasion by silencing the expression of metastasis suppressers such as Kiss-1 and NME-1. Furthermore, we have also shown that Wnt5A can mediate melanoma metastasis via the initiation of the epithelial to mesenchymal cell transition, in a PKC-dependent fashion. In addition, Wnt5A can suppress the expression of melanoma antigens, such as MART1, implying it may play a role in escape of tumor cells from immune surveillance. We are currently trying to understand the interaction of Wnt5A with its receptors, and the contribution of this to melanoma metastasis. Modulation of Wnt5A or its receptors may provide beneficial effects for patients, either when coupled with immunotherapy, or as single agents. Other molecules involved in melanoma progression under investigation in our laboratory include Notch proteins, Claudin-1, and ABCB transporter proteins.

Tumor cells: To grow or to go, that is the question: We believe that a tumor cell must channel its energy into one physiological process or another. Specifically, we believe that in order for a tumor cell to start metastasizing, it must first decrease its proliferative rate. Whether this occurs as an active arrest, or one induced by conditions of decreased nutrient supply, the net result, we believe, must be either death, or metastasis. We have previously shown that Wnt5A can increase melanoma metastasis. Gene expression profiling analysis revealed that Wnt5A induction causes the down-regulation of many genes. The few genes upregulated by Wnt5A include those involved in tumor cell metastasis such as CD44, and vimentin, involved in an epithelial to mesenchymal transition (EMT). Another gene upregulated upon Wnt5A overexpression was the gene p21, which can regulate cell cycle by inducing growth arrest. We have shown that p21 protein expression is also increased in a high wnt5a expressing melanoma cell line (M93-047) as compared to a low-expressing wnt5a expressing one (G361). Moreover, siRNA inhibition of Wnt5A results in a decrease in p21 expression in M93047 cells. We hypothesize that decreases in cell proliferation may coincide with increases in metastatic ability, and are using various tools with which to study this, including molecular and cellular analyses as well as animal studies.

Cancer and aging: a common thread?: Older individuals who present with cancer have a worse prognosis, and this could be due to factors such as decreased immunity, or changes in the microenvironment. Using melanoma cells and both young and old normal skin fibroblasts as a model, we are trying to unravel just what these changes may be, and how they affect tumor progression. We are currently using gene expression profiling analysis in conjunction with cellular analyses to determine if co-culturing melanoma cells with young vs. old fibroblasts has differing effects on their metastatic ability. We are inducing senescence in young fibroblasts to determine if senescing fibroblasts make melanoma cells more invasive. We are also asking if oncogene-induced senescence in tumor cells can influence surrounding cells in a co-culture system, make them senesce and in turn, release factors that then cause tumor cells to invade. Our current analyses implicate chemokines, Wnts, as well as aging-associated genes such as Klotho. All of these cellular and molecular studies will be examined in patient settings as well, where we will attempt to translate the changes we see between young and old cell culture systems to those in young and old patients.

Selected Publications:

O’Connell MP, Fiori JL, Baugher KM, Indig FE, French AD, Camilli TC, Frank BP, Earley R, Hoek KS, Hasskamp J, Elias G, Taub DD, Bernier M and Weeraratna AT (2008). Wnt5A Activates the Calpain-mediated Cleavage of Filamin A. Journal of Investigative Dermatology, In Press 2009.
French AD, Fiori JL, Camilli TC, Leotlela PD, O'Connell MP, Frank BP, Subaran S, Indig FE, Taub DD, Weeraratna AT (2009). PKC and PKA phosphorylation affect the subcellular localization of claudin-1 in melanoma cells. Int J Med Sci. 6(2):93-101.

Dissanayake SK, Olkhanud PB, O’Connell MP, Carter A, French AD, Camilli TC, Emeche CD, Hewitt KJ, Rosenthal DT, Leotlela PD, Wade MS, Yang SW, Nickoloff BJ, Messina JL, Biragyn A, Hoek KS, Brant L, Taub DD, Longo DL, Sondak VK, Hewitt SM and Weeraratna AT (2008). Wnt5A Regulates Expression of Tumor Associated Antigens in Melanoma Via Changes in STAT3 Phosphorylation. Cancer Res. 68(24):10205-14.
Dissanayake SK, Wade M, Johnson CE, O'Connell MP, Leotlela PD, French AD, Shah KV, Hewitt KJ, Rosenthal DT, Indig FE, Jiang Y, Nickoloff BJ, Taub DD, Trent JM, Moon RT, Bittner M, Weeraratna AT (2007). The Wnt5A/protein kinase C pathway mediates motility in melanoma cells via the inhibition of metastasis suppressors and initiation of an epithelial to mesenchymal transition.J Biol Chem 282:17259-71.
Leotlela PD, Wade MS, Duray PH, Rhode MJ, Brown HF, Rosenthal DT, Dissanayake SK, Earley R, Indig FE, Nickoloff BJ, Taub DD, Kallioniemi OP, Meltzer P, Morin PJ, Weeraratna AT (2007). Claudin-1 overexpression in melanoma is regulated by PKC and contributes to melanoma cell motility. Oncogene 26:3846-56
Weeraratna AT, Becker D, Carr KM, Duray PH, Rosenblatt KP, Yang S, Chen Y, Bittner M, Strausberg RL, Riggins GJ, Wagner U, Kallioniemi OP, Trent JM, Morin PJ, Meltzer PS (2004). Generation and analysis of melanoma SAGE libraries: SAGE advice on the melanoma transcriptome. Oncogene. 18;23(12):2264-74.

Weeraratna AT, Jiang Y, Hostetter G, Rosenblatt K, Duray P, Bittner M, Trent JM (2002). Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. Cancer Cell 1(3):279-88.

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