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.