Jimin Park
Research Mentor: Li-Jyun Syu
Mentor Department: Dermatology, Medicine
Author(s): Jimin Park, Li-Jyun Syu, Pei-Wei Huang, Zach Freeman, Andrzej Dlugosz
Session: Session 5 (2:00 PM – 2:50 PM)
Presentation Type: Poster 38
Abstract
Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer. Most MCCs contain a clonally integrated Merkel cell polyomavirus genome and express viral small tumor antigen (sTAg) and large tumor antigen (LTAg) that promote carcinogenesis. Intriguingly, essentially all human MCCs carry acquired mutations that produce truncated forms of LTAg (tLTAg), suggesting that expression of full-length LTAg (flLTAg) is not compatible with MCC tumorigenesis. All variants of tLTAg expressed in MCCs retain the LXCXE motif for binding and inhibiting the tumor suppressor pRb but they lose variable amounts of the LTAg C-terminus, which may impair tumorigenesis. To test this hypothesis and investigate potential mechanisms, we generated inducible mouse models of MCC to express several proteins, including viral sTAg and either tLTAg or flLTAg, designated tLTAg mice and flLTAg mice, respectively. Remarkably, 10 weeks after induction, tLTAg mice produced multiple macroscopic MCCs in the skin, whereas flLTAg mice did not. When the skin of flLTAg mice was examined at early time-points, MCC-like cells were detected, but they were lost over time, suggesting that tumorigenesis was initiated, but progression to macroscopic tumors failed. Increased numbers of cytotoxic T cells were detected in the skin of flLTAg mice, suggesting that the longer, full-length LTAg triggers an effective antitumor response in the skin to eliminate tumor cells. Strikingly, MCC-like tumors arose in flLTAg mice at other body sites with less active immune surveillance than skin, confirming that flLTAg is fully capable of driving tumorigenesis. These results strongly suggest that truncation of LTAg allows for MCC tumor progression in skin by overriding immunosurveillance that would eliminate cells expressing more immunogenic, flLTAg.
