Tissue Context Shapes Distinct Premalignant Outcomes in an HPV16 E6/E7-Mutant Pik3ca Transgenic Mouse Model

Area of Science:

• Oncology
• Molecular Biology
• Carcinogenesis

Background:

• High-risk human papillomavirus (HPV), especially HPV16, is a key cause of cancers like cervical and oropharyngeal carcinoma.
• Mechanisms of tissue-specific responses to HPV oncogene expression are not well understood.

Purpose of the Study:

• To develop a mouse model for studying HPV16 E6/E7 oncogene expression in specific epithelial tissues.
• To investigate the role of PI3K pathway activation in HPV-driven carcinogenesis.

Main Methods:

• Developed a double-inducible transgenic mouse model for controlled HPV16 E6/E7 expression in anal and oral mucosa.
• Combined the HPV16 E6/E7 model with a Pik3caH1047R knock-in model to study PI3K pathway cooperation.
• Analyzed epithelial hyperplasia, dysplasia, and lesion maintenance upon oncogene induction and withdrawal.

Main Results:

• HPV16 E6/E7 expression induced distinct premalignant lesions: low-grade in the anal canal and moderate-to-severe dysplasia in the tongue.
• Lesion maintenance required continuous oncogene expression; withdrawal reversed the phenotype.
• PI3K activation alone caused mild dysplasia; combined with E6/E7, it enhanced tongue dysplasia but not anal dysplasia.
• No invasive carcinoma developed within six months.

Conclusions:

• Identical oncogenic signals (HPV16 E6/E7, PI3K activation) yield distinct premalignant outcomes based on epithelial context.
• Local microenvironmental factors critically influence HPV-driven carcinogenesis.
• The model provides a platform for identifying tissue-specific therapeutic targets in HPV-associated cancers.