# Merkel cell polyomavirus T-Antigen mediated reprogramming in adult epidermis > **NIH NIH F31** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $47,374 ## Abstract 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 t... ## Key facts - **NIH application ID:** 10824742 - **Project number:** 1F31CA280993-01A1 - **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI - **Principal Investigator:** Madison Weber - **Activity code:** F31 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $47,374 - **Award type:** 1 - **Project period:** 2024-02-05 → 2028-02-04 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10824742 ## Citation > US National Institutes of Health, RePORTER application 10824742, Merkel cell polyomavirus T-Antigen mediated reprogramming in adult epidermis (1F31CA280993-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10824742. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*