Penile Cancer-Derived Cells Molecularly Characterized as Models to Guide Targeted Therapies.

Hellen Kuasne,Luisa Matos Do Canto,Mads Malik Aagaard,Sébastien Carréno,Fabio Albuquerque Marchi,Eliney Ferreira Faria,Silvia Regina Rogatto,Ademar Lopes,Juan Jose Moyano Muñoz,Camille De Jamblinne,Cristovam Scapulatempo-Neto

doi:10.3390/cells10040814

Abstract

Penile cancer (PeCa) is a common disease in poor and developing countries, showing high morbidity rates. Despite the recent progress in understanding the molecular events involved in PeCa, the lack of well-characterized in vitro models precludes new advances in anticancer drug development. Here we describe the establishment of five human primary penile cancer-derived cell cultures, including two epithelial and three cancer-associated fibroblast (CAF) cells. Using high-throughput genomic approaches, we found that the epithelial PeCa derived- cells recapitulate the molecular alterations of their primary tumors and present the same deregulated signaling pathways. The differentially expressed genes and proteins identified are components of key oncogenic pathways, including EGFR and PI3K/AKT/mTOR. We showed that epithelial PeCa derived cells presented a good response to cisplatin, a common therapeutic approach used in PeCa patients. The growth of a PeCa-derived cell overexpressing EGFR was inhibited by EGFR inhibitors (cetuximab, gefitinib, and erlotinib). We also identified CAF signature markers in three PeCa-derived cells with fibroblast-like morphology, indicating that those cells are suitable models for PeCa microenvironment studies. We thus demonstrate the utility of PeCa cell models to dissect mechanisms that promote penile carcinogenesis, which are useful models to evaluate therapeutic approaches for the disease.

Highlights

Using oncogenic signatures (Figure 3C) and the Reactome (Figure 3D) sub-collection of the MSigDB, we identified that EGFR, PI3K, and mTOR pathways were dysregulated in cell 2
Having shown that EGFR inhibition can block the proliferation of penile cancer (PeCa) cells in vitro, we evaluated whether PeCa primary tissues overexpress the EGFR gene
We identified a cluster of samples (~30% of the cases) showing EGFR mRNA signature overexpression (Figure 5A,B)

Summary

Introduction

Penile cancer (PeCa) is an aggressive and mutilating disease that presents a high incidence in poor and developing countries [1,2]. According to two population-based cancer registry surveys, the survival of PeCa patients has not improved in Europe or the United States in the last three decades [3,4]. Genetic and epigenetic alterations associated with PeCa development and progression have pointed out potential therapeutic targets (reviewed in [6,7]). In the last few years, we have reported molecular markers and deregulated pathways that are potentially helpful for discovering such targets in PeCa [8–11]. The scarcity of in vitro or animal models emerges as an obstacle that hampers the establishment of new and efficient therapeutic strategies for PeCa [12]

Methods

Results

Conclusion