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

YAP1-LATS2负反馈环路在宫颈癌发生中的作用

• 批准号: 10635529
• 负责人: Cheng Wang
• 金额: $ 41.96万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10635529
• 关键词: Achievement; Animal Model; Automobile Driving; Biological Markers; Cancer Etiology; Cell Senescence Induction; Cells; Cervical; Cervical Cancer Screening; Cervical Intraepithelial Neoplasia; Cervical Squamous Cell Carcinoma; Cervix Neoplasms; Cessation of life; Clinical Trials; DNA Sequence Alteration; Development; Diagnosis; Epithelial Cells; Epithelium; Feedback; Gene Expression Profiling; Genes; Genetic; Genomics; Growth; HPV-High Risk; Homeostasis; Human; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Immunotherapeutic agent; In Vitro; Intrinsic factor; Knowledge; LATS2 gene; Laboratories; Lesion; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Molecular; Mouse Strains; National Cancer Institute; Natural Immunity; Neoplasms; Oncoproteins; Pap smear; Pathologic; Pathway interactions; Phosphotransferases; Physiological; Play; Prevention; Prevention strategy; Recurrence; Research; Role; Sensitivity and Specificity; Signal Pathway; Signal Transduction; Solid; Survival Rate; System; Technology; Testing; Transgenic Animals; Transgenic Mice; Translating; United States; Viral; Woman; Xenograft procedure; base; cancer invasiveness; cervical carcinogenesis; design; high risk population; improved; in vivo Model; mouse model; new technology; new therapeutic target; novel; novel therapeutics; pharmacologic; preclinical study; premalignant; public health relevance; receptor; role model; screening; senescence; single cell sequencing; single-cell RNA sequencing; success; tumor progression

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.

摘要：在全球范围内，每年约有570,000名妇女被诊断患有宫颈癌（CVC）