Abstract

Cancer is a disease of aging. Most cancers arise after the age of 50, and in our increasingly aging population, this poses a significant public health burden. The molecular mechanisms that underlie the age-induced progression of cancer are not well understood. We have discovered that aged fibroblasts in the tumor microenvironment secrete, or stop secreting, key molecules that affect multiple aspects of tumorigenesis. These include: the loss of molecules that maintain ECM integrity, resulting in changes in mechanotransduction and increased metastasis; the secretion of molecules that increase resistance to targeted therapy; the uptake of macromolecules such as lipids by melanoma cells in the aged microenvironment, affecting tumor cell metabolism; changes in the aged immune tumor microenvironment and the secretion of non-canonical Wnt molecules that affect cell signaling leading to angiogenesis, metastasis, and therapy resistance. These changes drive tumor progression and affect response to therapy in the elderly. Our data suggest that patient age is an important factor in the response to therapy, which is not reflected in most preclinical studies and therapeutic approaches.

Speaker Bio

Dr. Weeraratna is currently the E.V. McCollum Chair of Biochemistry and Molecular Biology at the Johns Hopkins School of Public Health, a Bloomberg Distinguished Professor, and Co-Program Leader of the Cancer Invasion and Metastasis Program at the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine. Prior to joining Johns Hopkins, she was the Ira Brind Professor and Co-Program Leader, Immunology, Microenvironment & Metastasis Program Member at the Wistar Institute. Born in Sri Lanka and raised in Southern Africa, Weeraratna first came to the United States in 1988 to study biology at St. Mary’s College of Maryland. She earned a Ph.D. in Molecular and Cellular Oncology at the Department of Pharmacology of George Washington University Medical Center. From 1998 to 2000, she was a post-doctoral fellow at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Oncology Center, before joining the National Human Genome Research Institute as a staff scientist. In 2003, she moved to the National Institute on Aging, where she started her own research program, before joining the Wistar Institute from 2011-2019. Dr. Weeraratna is an expert in melanoma metastasis, Wnt signaling, and aging, and her research focuses heavily on the effects of the tumor microenvironment on metastasis and therapy resistance. She is one of the first to study how the aging microenvironment guides metastasis and therapy resistance in melanoma. Her studies encompass biopohysical 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. The Weeraratna laboratory has 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, as they are finding age-related differences in responses to both targeted and immunotherapy. Dr. Weeraratna is using these proteomics data to guide further studies on how the aging microenvironment affects tumor dormancy and cellular metabolism.

Through speaking engagements and social media, Dr. Weeraratna diligently promotes skin safety, from urging proper sunscreen use to regular mole checks, as well as the dangers of indoor tanning. She is also a fierce champion of and a mentor for junior faculty, women in science and girls pursuing a science, technology, engineering, and math (STEM) education.