Summary Oral cavity squamous cell carcinoma (OCSCC), the most common subtype of head and neck squamous cell carcinoma (HNSCC), is a devastating disease, causing substantial morbidity and mortality. Consumption of alcohol and tobacco products increases the risk of OCSCC. Prevalence of human papilloma virus (HPV) infection outside of oropharyngeal cancer is low, and its significance remains debatable. Only a handful of targeted therapies are available for patients with HPV-negative HNSCC (which include many oral cavity cancers), and the 5-year overall survival remains ~50%. While strategies are being designed to improve risk assessment, detection, and therapeutic intervention, these approaches are limited by our incomplete understanding of HNSCC biology, particularly in its early development. Thus, it is crucial to identify novel targets of therapeutic interest. PDCD10 is a multifaceted protein shown to be overexpressed in several solid malignancies. It was reported that PCDC10 regulates numerous oncogenic pathways and may contribute to tumorigenesis and chemoresistance by promoting cell proliferation, anti-apoptosis, epithelial-mesenchymal transition, and inhibiting anti-tumor immune responses. Recently it was suggested that PDCD10 is involved in regulating cancer stem cells (CSCs) maintenance in breast and lung cancers. In line with these observations, our studies suggest that PDCD10 plays an important role in promoting Wnt/β-catenin mediated stem cell maintenance in small intestines. Notably, preliminary data outlined below provide strong evidence for an equivalent role of PDCD10 in HNSCC, and suggest that upregulation of its expression is an important event in neoplastic progression, posing PDCD10 as a valuable prognostic biomarker and a potential therapeutic target. While PDCD10 is being actively studied in several preclinical settings, there is limited data on its role in head and neck tumorigenesis. In this proposal we will use in vivo and organoid based preclinical models, coupled with comprehensive bioinformatics analysis of longitudinally collected primary human specimens, to evaluate the role of PDCD10 in HNSCC evolution and driving aggressive tumor cells behavior. Our project pursues three independent Aims. Specifically: Aim 1 will use mice model with inducible Pdcd10 knockout in tongue epithelia to evaluate the ability of PDCD10 depletion to inhibit oral cancerogenesis in vivo; Aim 2 will use human OCSCC organoid models to assess the ability of PDCD10 to promote CSCs survival and self-renewal; while Aim 3 will use a unique already existing RNA-Seq dataset of longitudinally collected oral dysplastic lesions and OCSCC samples to delineate key PDCD10 dependent signaling pathways that drive malignant transformation. Given the devastating nature of HPV- HNSCC and dearth of effective treatment approaches, providing new insights into the cancer driving molecular mechanisms regulated by PDCD10 and using this knowledge for developing therapeuti...