An Assessment of the Penile Squamous Cell Carcinoma Surfaceome for Biomarker and Therapeutic Target Discovery

SIMPLE SUMMARY: Penile cancer is considered a rare disease in most developed countries, yet it represents a significant global oncology challenge. Many patients are faced with substantial psychosocial morbidity from diagnosis and treatment, which is further compounded by a lack of access to novel treatment approaches when the disease becomes resistant to upfront therapies. Proteins on the cell surface, or surfaceome, represent an accessible locale of potential biomarkers and therapeutic targets. This study provides the first description of the surfaceome in penile cancer and evaluates if human papillomavirus infection contributes to surfaceome diversity. ABSTRACT: Penile squamous cell carcinoma (PSCC) is a rare malignancy in most parts of the world and the underlying mechanisms of this disease have not been fully investigated. About 30–50% of cases are associated with high-risk human papillomavirus (HPV) infection, which may have prognostic value. When PSCC becomes resistant to upfront therapies there are limited options, thus further research is needed in this venue. The extracellular domain-facing protein profile on the cell surface (i.e., the surfaceome) is a key area for biomarker and drug target discovery. This research employs computational methods combined with cell line translatomic (n = 5) and RNA-seq transcriptomic data from patient-derived tumors (n = 18) to characterize the PSCC surfaceome, evaluate the composition dependency on HPV infection, and explore the prognostic impact of identified surfaceome candidates. Immunohistochemistry (IHC) was used to validate the localization of select surfaceome markers. This analysis characterized a diverse surfaceome within patient tumors with 25% and 18% of the surfaceome represented by the functional classes of receptors and transporters, respectively. Significant differences in protein classes were noted by HPV status, with the most change being seen in transporter proteins (25%). IHC confirmed the robust surface expression of select surfaceome targets in the top 85% of expression and a superfamily immunoglobulin protein called BSG/CD147 was prognostic of survival. This study provides the first description of the PSCC surfaceome and its relation to HPV infection and sets a foundation for novel biomarker and drug target discovery in this rare cancer.