Credentialing a Mouse Model for Merkel Cell Carcinoma
Abstract
Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine carcinoma with an estimated incidence of 0.2 to 0.7 per 100,000 annually in the United States with high lethality. There are two established etiologies: the more common one is due to integration of an altered Merkel cell polyomavirus genome with the expression of viral oncoproteins, and in the second, characteristic mutations in RB1 and TP53 occur in the context of high tumor mutation burden and a preponderance of UV signature mutations. Our main objective is to credential a novel, first in kind, mouse model of virus-negative MCC using removal of Rb1, Trp53 and overexpression of c-Myc and to identify and test the relevance of key pathways implicated in virus-negative MCC. Our central hypotheses are that keratinocytes can be a cell of origin for Merkel cell carcinoma, that the resulting tumors recapitulate the human disease, and the Sleeping Beauty transposon system identifies genetic enhancers and suppressors. We propose to address these this in two AIMS: Aim 1: Credential our novel model of Merkel cell carcinoma using genomics and immunohistochemistry. Aim 2: Identify cooperating events through superimposed transposon mediated mutagenesis. We have shown a close relationship with human SCC and neuroendocrine tumors such as small cell lung carcinoma. In addition, we have shown that varying levels of neuroendocrine differentiation are present across both human and mouse MCC tumors and cell lines. Pending work will address challenges we have faced with transposon mediated mutagenesis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1223080
Entities
People
- Kenneth Y. Tsai
Organizations
- H. Lee Moffitt Cancer Center & Research Institute