Login to Access Video or Poster Abstract: MP81-07
Sources of Funding: None

Introduction

Penile cancer is rare but fatal malignant disease. The predominant histologic type of penile cancer is squamous cell carcinoma. The molecular mechanism of penile cancer has not been extensively studied thus far and remain poorly understood. We present the first genetically engineered penile cancer model in mice that represents a model for studying molecular mechanisms and pathway alterations in penile cancer pathogenesis

Methods

Two transgenic models that develop penile cancer through tissue-specific deletion of tumor suppressor genes were generated in a background nearly congenic to C57BL/6: deletion of smad4;Apc (model 1) and deletion of smad4;Apc; Pten (model 2). Penile prolapse was the phenotype of penile cancer formation. Tumor histology was confirmed by two pathologists (P.T., P.R.). Established penile tumors were harvested for RNAseq, reverse phase protein array (RPPA) and mass cytometry (CyTOF) for analyses if transcriptome, targeted proteome and immunophenotyping, respectively. In vivo treatment of mouse primary penile tumors was performed in 6 mice/group using cisplatin chemotherapy

Results

Smad4; Apc mice developed primary penile tumors at 18-20 weeks of age, whereas Smad4; Apc; Pten mice develop tumors at 8-10 weeks. The tumors resembled penile squamous carcinoma by pathologic confirmation. In vivo treatment of mice with cisplatin revealed that that Pten loss could mediate tumor resistance to cisplatin treatment. CyTOF analysis showed a strong inflammatory phenotype of the tumors with massive infiltration of CD11b+ Gr1+ myeloid cells. Transcriptomic analysis indicates that COX-2 may be the master regulator of the inflammatory phenotype. RPPA analysis showed a number of highly regulated proteins and pathways in Smad4;Apc tumors compared with normal penis. Based on RPPA result, we are currently testing sensitivities of isolated penile cancer cell lines to a panel of 50 drugs, targeting molecules involved in pathways such as PI3K/AKT/mTOR, HER2/EGFR, SRC, JAK, STAT3, Bcl-XL, etc. We have also developed 4 penile cancer PDX models, and isolated penile cancer cell lines that grow squamous cell carcinoma in SCID mice from 2 of the 4 models. The PDX and cell lines will help validate our findings from transgenic mouse models.

Conclusions

A genetically engineered penile cancer mouse model was developed exhibiting a histologic and molecular phenotype that resembles human penile cancer. This model may assist in studying the mechanisms of tumor pathogenesis, progression and novel therapeutic strategies

Funding

None