Investigating the Role of MYC in Meibomian Gland Oncogenesis - PROJECT SUMMARY/ABSTRACT Sebaceous carcinomas (SebCA) of the ocular adnexa (OA) most frequently arise from the specialized sebaceous glands of the eyelid (Meibomian glands, MGs), and commonly exhibit local invasiveness with intraepithelial spread into the conjunctiva. These aggressive features complicate complete surgical excision and increase the risk for distant metastasis, resulting in a mortality rate of up to 40% of affected patients. While alterations in TP53 and/or RB1 and syndromic loss-of-function mutations in mismatch repair genes have been associated with OA SebCA, the genomic landscape of this tumor remains largely unresolved. I recently demonstrated MYC overexpression in a subset of OA SebCA, both with and without amplification at the MYC locus, and many of the high-MYC tumors also harbored mutations and copy number alterations in components of the insulin/insulin-like growth factor signaling (IIS) pathway. The effects of dysregulated IIS on MYC expression and malignant transformation of the MG remain unresolved, and MYC overexpression as driver of OA SebCA has not been previously evaluated. The hypothesis underlying this proposal is that MYC overexpression in meibocytes is initiated through dysregulated IIS, resulting in enhanced proliferative potential and cell survival in addition to local immunosuppression. I further predict that MYC overexpression, alone, is insufficient for malignant transformation of meibocytes, requiring the acquisition of tumor suppressor mutation. As such, the objectives of this proposal are to determine the role of IIS on MYC expression in meibocytes, characterize the molecular and transcriptomic changes associated with IIS modulation in meibocytes, understand the impact of both on cells in the local microenvironment, and define the temporal relationship between MYC overexpression and TP53 loss-of-function with respect to malignant transformation of the MG in vivo. To accomplish this, Aim 1 will assess the impact of pharmacologically and genetically modulated IIS on cell behavior, transcriptional landscape, and MYC expression in normal and neoplastic meibocytes in vitro, while Aim 2 will define the effects of modulated MYC expression on phenotypic features and the transcriptional landscape of normal and neoplastic meibocytes in vitro. Additionally, the consequences of MYC overexpression, in the presence or absence of Trp53 inactivation, on the MG and local microenvironment will be determined using genetically engineered mouse models. The rich research environment afforded by Tufts University, the Tufts Clinical Translational Science Institute, and associated partners ensures access to resources and expertise necessary for completion of the proposed work. My training in veterinary pathology, vision science, and molecular biology, along with guidance from my mentoring team with expertise in comparative immuno-oncology, pathology, IIS, and MYC biology, will facilitate successful completion of milestones outlined in this application and the transition to an independent clinician scientist in the field of comparative ocular pathology and oncology.
