Role of the YAP1-LATS2 negative feedback loop in cervical carcinogenesis

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Summary: Globally, around 570,000 women are diagnosed with cervical cancer (CVC) each year, resulting in more than 310,000 CVC-related deaths in women annually. In the United States, the National Cancer Institute estimates that approximately 290,000 women are currently living with CVC. The five-year overall survival rate for recurrent or metastatic CVC is lower than 20%. Although previous studies identify high-risk human papillomavirus (hrHPV) as a causative agent of CVC, the vast majority of HPV-induced pre-cancer lesions eventually regress, suggesting that HPV alone is insufficient to cause CVC. Unknown intrinsic factor(s) associated with the genetic/genomic alterations of the high-risk population likely play a critical role in the progression of HPV-induced cervical intraepithelial neoplasia (CIN) and cervical carcinogenesis. Our recent preliminary studies demonstrate that YAP1 (a major effector of the Hippo signaling pathway) and LATS2 (a key kinase and upstream YAP1 suppressor in the Hippo signaling cascade) form a YAP1-LATS2 negative feedback loop to maintain homeostasis of the cervical epithelium. Importantly, we observed that although HPV16 E6/E7 failed to induce malignant transformation of primary human cervical epithelial cells (HcerECs), they successfully induced malignant transformation of HcerECs with a disrupted YAP-LATS2 feedback loop, leading to the development of cervical squamous cell carcinoma (CSCC). Based on these observations, we hypothesize that a functional YAP1-LATS2 negative feedback loop is essential for maintaining the homeostasis of the cervical epithelium, and the disrupted YAP1-LATS2 feedback loop is a previously unprecedented mechanism underlying the progression of hrHPV-induced cervical intraepithelial neoplasia. In this proposed project, we will create novel transgenic mice to model the role of the disrupted YAP1-LATS2 negative feedback loop in the formation and progression of HPV-induced CINs (Aim 1), examine the mechanisms by which the disrupted YAP1-LATS2 loop drives pre-cancer lesion progression (Aim 2), and test whether targeting the disrupted YAP1-LATS2 loop has the potential to improve the prevention and treatment of CSCC (Aim 3). The achievement of the proposed studies is expected to recognize the disrupted YAP1-LATS2 feedback loop as a previously unprecedented mechanism underlying the progression of cervical neoplasia and carcinogenesis of the cervical epithelium. The combination of new technologies such as single-cell RNA sequencing with our unique physiological/pathological relevant transgenic animal models is expected to identify key genes and pathways involved in the formation and progression of HPV-induced pre-cancer lesions and the development of cervical cancer. Research results derived from the proposed preclinical studies will provide a solid base for developing new drugs and strategies to improve the prevention and treatment of human CSCC.