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Ashani T. Weeraratna, PhD

  • Chair, Biochemistry & Molecular Biology
  • Bloomberg Distinguished Professor
  • Professor

Departmental Affiliations

Contact Information

615 N. Wolfe Street
Room E3132
Baltimore, Maryland 21205

410-955-3655

View Current Courses

Education

PhD, The George Washington University Medical Center, 1998
BA, St. Mary's College of Maryland, 1991

Overview

My laboratory focuses on trying to unravel the molecular mechanisms that lead to metastatic progression and therapy resistance. We are investigating the link between changes in the tumor microenvironment and melanoma progression, and further, how these changes may affect response to therapy. More recently, we have become very interested in how the aging microenvironment guides changes leading to increased metastasis and therapy resistance, as well as cell-autonomous aspects of therapy resistance, and have demonstrated that normal age-related changes in the microenvironment can contribute to multiple aspects of melanomagenesis and therapy resistance.

My early publications identified the non-canonical Wnt signaling molecule Wnt5A as a key driver of melanoma metastasis. Previously, this molecule was not associated with melanoma. Studies from my laboratory have shown how Wnt5A is critical in driving cytoskeletal changes, driving an EMT and promoting invasion via PKC and Calcium activated downstream mediators, and surprisingly, by suppressing b-catenin signaling. My research on the non-canonical Wnt signaling pathway in melanoma and its regulation of key melanocyte differentiation antigens has provided a biological basis for the theory of “phenotype switching” in melanoma. This hypothesis purports that tumor cells make a choice between growing or metastasizing. My studies have shown that Wnt5A signals to disable the beta-catenin pathway and drive invasion, and highlight the antagonistic roles that different Wnt molecules play during melanoma growth and progression. More recently, we have shown that the molecular mechanisms that underlie metastasis can also dictate response to therapy. We show that these changes are driven by changes in the microenvironment such as hypoxia. We also define a novel cellular state that we call “pseudosenescence” that is an adaptive stress response to therapeutic stress. This cell fate is driven by p21 and is defined as a state that bears all of the experimental hallmarks of senescence upon therapeutic, but retains metastatic capacity, and represents a highly resistant cell state.

My laboratory is one of the first to study how the aging microenvironment guides metastasis and therapy resistance in melanoma. Our studies encompass biophysical changes that affect the ability of both tumor and immune cells to migrate, that affect vasculature integrity thus dictating routes of metastasis, and also secreted changes that drive metastatic signaling and response to therapy. We have also undertaken a global analysis of how the aged microenvironment promotes metastasis, using a unique resource of normal skin fibroblasts from healthy donors of differing ages, proteomics analysis, and animal models. The clinical implications of these data may also result in a change in clinical practice, we are finding age-related differences in responses to both targeted and immunotherapy. We are using these proteomics data to guide further studies on how the aging microenvironment affects tumor dormancy and cellular metabolism.

  • Cancer
  • Aging
  • Metastasis
  • Melanoma
  • Matrix
  • Wnt
  • Wnt5A

Selected publications from the last 5 years. My laboratory focuses on trying to unravel the molecular mechanisms that lead to metastatic progression and therapy resistance. We are investigating the link between changes in the tumor microenvironment and melanoma progression, and further, how these changes may affect response to therapy. More recently, we have become very interested in how the aging microenvironment guides changes leading to increased metastasis and therapy resistance, as well as cell-autonomous aspects of therapy resistance, and have demonstrated that normal age-related changes in the microenvironment can contribute to multiple aspects of melanomagenesis and therapy resistance.

  • Kaur A, Webster MR, Marchbank K, Behera R, Ndoye A, Kugel III CH, Dang VM, Appleton J, O’Connell MP, Cheng P, Valiga AA, Morissette R, McDonnell NB, Ferrucci L, Kossenkov AV, Meeth K, Tang H-Y, Yin X, Wood III WH, Lehrmann E, Becker KG, Flaherty KT, Frederick DT, Wargo JA, Cooper ZA, Tetzlaff MT, Hudgens C, Aird KM, Zhang R, Xu X, Liu Q, Bartlett E, Karakousis G, Eroglu Z, Lo RS, Chan M, Menzies AM, Long GV, Johnson DB, Sosman J, Schilling B, Schadendorf D, Speicher DW, Bosenberg M, Ribas A, and Weeraratna AT. 2016. sFRP2 in the aged microenvironment
  • B.L. Ecker, A. Kaur, S. Douglass, M.R. Webster, F.V. Almeida, A.J. Sinnamon, M.G. Neuwirth, A. M. Ndoye, G.M. Alicea, M. Fane, X. Xu, G.C. Karakousis, A.T. Weeraratna. Age-Related Changes in Lymphatic Permeability May Dictate Routes of Melanoma Metastasis. Cancer Discovery, 9(1):82-95.
  • CH Kugel 3rd, Douglass SM, MR Webster, A Kaur, Q Liu, X Yin, S Weiss, F Darvishian, RN Al-Rohil, A Ndoye, R Behera, G Alicea, M Fane, B. Ecker, MJ Allegrezza, N Svoronos, V Kumar, D Wang, R Somasundaram, S Hu-Lieskovan, M Herlyn, JR Conejo-Garcia, DI Gabrilovich, EL Stone, TS Nowicki, W Xu, Amaravadi R, JA Sosman, R Marais, A Ribas, Z Eroglu, MA Davies, B Schilling, D Schadendorf, AM Menzies, J McQuade, DB Johnson, I Osman, & AT Weeraratna. Age-related differences in intra-tumoral Tregs dictate response to anti-PD1. Clin Cancer Res,24(21):5347-5356
  • Kaur A, Ecker BL, Douglass SM, Kugel CH III, Webster MR, Somasundaram R, Hayden J, Ban E, Ahmadzadeh H, Franco-Barraza J, Shah N, Mellis I, Keeney F, Kossenkov AV, Tang HY, Yin X, Liu Q, Xu X, Brafford P, Herlyn M, Speicher DW, Raj A, Cukierman E, Shenoy VB, and Weeraratna AT. Remodeling of the collagen matrix in aging skin promotes melanoma metastasis, while impeding immune cell motility. Cancer Discovery, 9(1):69-81
  • Fane M and Weeraratna A.T. How Ageing Drives Tumor Progression. Nature Reviews in Cancer, 2019, In Press.