Abstract
Purpose :
Sebaceous carcinoma (SC) is an aggressive malignancy derived from the sebaceous glands in the ocular adnexa. It has a high propensity for pagetoid spread, but no standardized pharmacological treatments currently exist. Patients often require orbital exenteration to prevent metastasis. A significant barrier to therapeutic advances is our gap of knowledge in cellular and molecular changes underlying SC tumor progression. Here, we performed single-cell RNA sequencing (scRNA-seq) to develop a detailed understanding of SC tumor microenvironment, profiling immune and tumor cells across tumorigenesis and local invasion.
Methods :
scRNA-seq was performed on three primary SC tumor specimens, two pagetoid spread specimens, and one normal control specimen. Clustering and cell type identification was performed. Immune cells were assessed for expression of genes associated with cancer immunomodulators that are FDA-approved or currently undergoing clinical trials. Differential gene expression and gene ontology analysis was performed with sebocytes and tumor cells to identify pathways underlying tumor progression. Differentially expressed genes were also inputted into the Library of Integrated Network-Based Cellular Signatures (LINCS) program to predict candidate small molecules for reversing disease signatures.
Results :
Integrated analysis across three stages of SC progression reveals a heterogeneous microenvironment with a high degree of immune infiltration, despite its pauci-mutational status and lack of apparent chromosomal additions or deletions. Curiously, CTLA4 and its receptor are highly expressed in subsets of immune cells, highlighting the potential for anti-CTLA4 therapies in future studies. Gene ontology analysis provided insight into tumor progression. Compared to sebocytes, primary tumor cells have identified increased mitotic nuclear division and oxidative phosphorylation pathways and decreased lipid biosynthesis pathways. As tumor cells progress to pagetoid spread, they have upregulated epithelial tissue migration gene pathways. LINCS analysis identified proteasome inhibitors and epigenetic modifiers as potential perturbagens for reversing these disease signatures.
Conclusions :
Our study provides insight to SC’s complex tumor microenvironment and highlights the utility of our dataset in therapeutic discovery. Further in vitro studies are needed to confirm these findings.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.