Deploying a Novel Model of Merkel Cell Carcinoma for Development of Novel Therapeutic Approaches
Abstract
There is no reported molecularly faithful model of UV-Merkel cell carcinoma. Such a model enables the exploration of cells of origin, cooperating genetic events, the role of the immune system, and serves as a preclinical platform for testing new therapies. Successful completion of this project will produce a quantum leap in our collective capability to study this disease from etiology on through to therapeutic intervention. The validation of these hypotheses and credentialing of a novel, first in kind, mouse model of non-viral MCC will make available to the community an extremely valuable resource. The vast majority of activities are related to ensuring that we are in a position to produce all the intermediate strains needed on an inbred C57BL/6 background. We are still in a position to complete the SOW as listed. We have made significant progress in Major Subtasks 2, 3, 6, 7. Our main objective is to credential a novel, first in kind, mouse model of virus-negative MCC and to test the relevance of key pathways implicated in virus-negative MCC and responses to immunotherapy. Along these lines, we have generated key data related to initial characterization of how UV exposure accelerates tumorigenesis, linkage to human MCC, and initial FACS analysis of the tumor microenvironment. First, we have clearly shown that UV-exposure using a 3 month course of low dose UV irradiation (Newport Solar Simulator) dosed at 12.5 kJ/m2 weekly (broad band UVB) accelerates tumor formation in RPM mice. Next, we have performed some immunohistochemistry on our samples to show evidence of neuroendocrine differentiation (INSM expression) in mouse MCC tumors from RPM mice. This is accompanied by KRT8 expression, focal ATOH1 expression, consistent with MCC tumors.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1219925
Entities
People
- Kenneth Y. Tsai
Organizations
- H. Lee Moffitt Cancer Center & Research Institute