Monday, April 29, 2024
4/29/2024
ABSTRACT Merkel cell carcinoma (MCC) is a poorly understood cutaneous malignancy with viral etiology. Most MCC tumors feature monoclonal integration of Merkel cell polyomavirus (MCV), which expresses viral T-Antigens (T-Ags). Small T-antigen (sT-Ag) acts as a transcriptional co-regulator, while Large T (LT-Ag) principally functions to sequester retinoblastoma protein (RB1) to de-regulate the cell cycle. The T-Ags are responsible for driving tumorigenesis in T-Ag expressing (T-Ag+) MCC tumors: few mutations are present in T-Ag+ MCC tumors, including in tumor suppressors RB1 and TP53, whose activities are instead repressed by the functions of the T- Ags. Latent MCV infection that doesn’t result in T-Ag production is found in a substantial portion of the human population, however MCC occurs only rarely. Much of what occurs between latent infection and the appearance of a full-blown T-Ag+ MCC tumor has not been explored due to the lack of in vivo MCC tumorigenesis models. Among the unanswered questions is how the MCV T-Ags induce a tumor transcriptional program that features markers of multiple cell lineages, including both epidermal stem cell and neuroendocrine fates. Previous research in our laboratory determined that SOX9-expressing (SOX9+) hair follicle cells, which give rise to mechanosensory Merkel cells during fetal development, are also Merkel cell progenitors in adult skin. Hypothesizing that T-Ags reprogram cells in the Merkel cell lineage to cause MCC, I generated transgenic mice that express sT-Ag and ablate RB1 to mimic LT-Ag in SOX9+ cells. These mice developed tumors that were not bona-fide MCC but expressed neuroendocrine markers, making these mice a valuable model in which to study mechanisms of T-Ag mediated reprogramming. Analysis of tumors at early time points revealed that re- programming occurred only in specific sub-populations of SOX9+ cells and that reprogrammed cells were highly apoptotic. Therefore, I hypothesized that specific landscapes of gene accessibility are required for T-Ags to induce reprogramming from an origin cell and that suppressing p53 mediated apoptosis is required for MCC. I propose to leverage the model of SOX9-derived, T-Ag driven neuroendocrine tumors to generate novel insights into the mechanisms of T-Ag mediated reprogramming. I will use integrated epigenetic and transcriptomic sequencing analyses to characterize the gene accessibility and transcriptional landscape required for T-Ag mediated reprogramming to occur and identify a native cell type that is competent to undergo reprogramming. Furthermore, I will study how p53 suppression, which is commonly observed in MCC tumors, contributes to advancing reprogramming. Altogether, the proposed studies will establish a model of T-Ag mediated reprogramming in vivo and discover factors that enable T-Ags to reprogram cells. This research will not only make valuable contributions to the field of MCC research but also to my training by exposing me to molecular techniques and genomic and epigenomic analyses that are foundational to an independent research career.
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