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Monday, April 9 • 4:15pm - 4:30pm
LANDSCAPE PATTERN & PROCESS: Local Environmental Constrains and Chronic UV Exposure as Key Regulators of Normal Keratinocytes Immortalization and Transformation

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AUTHORS: Stanislav Avdieiev*, Kenneth Tsai, Joel Brown, Robert Gatenby – H. Lee Moffitt Cancer Center & Research Institute.

ABSTRACT: Skin cancer is the most common form of malignancy in humans. Despite of the growing body of studies, first principles and basic molecular aspects of initiation and progression of this malignancy is still poorly understood. In this study, we are investigating the evolutionary and molecular principles that can help to explain the establishment, dynamic, and long-term outgrowth of cancer cell clones in skin following chronic UV exposure. Our central hypothesis is that skin cancer is induced not by solely accumulation of genetic mutations, but rather combination of mutations and disruption of the spatial and temporal constraints imposed by the 3-D architecture of skin. Recent ultra-deep sequencing studies have demonstrated that adult sun-exposed skin is a patchwork of clones with common cancer-driving mutations, however, it is still physiologically normal skin. One explanation is that local tissue landscape plays a pivotal role in the skin clonal architecture. Epidermal progenitor cell compartments constitute physical barriers to expansion of p53-mutant keratinocytes. Subsequently, adjacent tissue space provides a valuable resource that permit unusually long rounds of proliferation of mutants. Sunlight can act as a tumor promoter by killing normal cells but sparing the P53-mutated cells since they are resistant to UV-induced apoptotic death. After surviving irradiation, these mutant cells could then clonally expand into vacated compartments.Our study are focused on testing the roles of mutational load and cell turnover (proliferation) on the emergence of malignant phenotypes in-vitro and in-vivo using chronic UV-exposure and live-imaging of primary human keratinocytes, intravital microscopy of K14 keratinocytes in mice, CRISPR functional genomics, signaling profiling and exome sequencing of selected clones. Taken together, our research is aimed to understand, explain and predict the earliest step of carcinogenesis driven by chronic UV exposure.

Monday April 9, 2018 4:15pm - 4:30pm CDT
Spire Parlor

Attendees (2)