PROJECT SUMMARY/ABSTRACT Squamous cell carcinoma is a major cause of death worldwide. Despite advances in cancer genetics, alterations in post-translational modifications are poorly understood. Protein glycosylation is the most abundant PTM and altered in cancer. Glycans are not directly encoded in the genome but rather are comprised of up to ten monosaccharides in various linkages to form thousands of structures, making their structural and functional characterization challenging and largely unknown in SCC. To address this, I propose to use murine skin as a highly tractable model system to study altered glycosylation, downstream consequences, and identify novel therapies. In the K99, I will use glycan binding proteins, metabolic labeling, advanced microscopy, MALDI imaging, glycomics, glycoproteomics, and single cell transcriptomics to spatially map glycosylation and identify specific glycan and glycoprotein changes in a genetic, multi-hit, histologically progressive model of SCC from papilloma to SCC, before chemotherapy, and after recurrence (Aim I). Next in the K99, I will use our in utero lentivirus technology to transduce epidermis and perform a large-scale, unbiased, in vivo, functional genomics screen of the ~700 glycogenes to define the role of glycosylation in SCC (Aim II). Lastly in the R00, I will combine glycoproteomics, single cell transcriptomics of the tumor and microenvironment, protein-specific glycan editing, and high-throughput drug screens to identify mechanisms of glycan-driven tumorigenesis and novel therapeutic candidates (Aim III). My background in glycobiology, medical oncology, and mentorship from leading skin and cancer biologist Dr. Elaine Fuchs at the outstanding training environments at Rockefeller University and Memorial Sloan Kettering Cancer Center, as a postdoctoral and medical oncology fellow, will position me to tackle these important questions and learn techniques, knowledge, and leadership to establish a career as a leading independent investigator and physician-scientist in cancer glycobiology.

PROJECT NARRATIVE Squamous cell carcinoma is a major cause of mortality, but despite breakthroughs in genetics, little is known about the role of post-translational modifications, including the most abundant PTM protein glycosylation. In this proposal, I will use murine skin as a highly tractable model system to investigate SCC glycosylation. By discovering how carbohydrates change in SCC and the downstream consequences, my work has the potential to dramatically improve our understanding of SCC and identify new therapeutic opportunities.