Role of USP13 in Histologic Transformation in Cancer and Therapeutic Resistance

Lung squamous cell carcinoma (LUSC) is associated with high mortality and limited targeted therapies. Ubiquitin-specific peptidase 13 (USP13) belongs to the deubiquitinating enzyme family, which removes the ubiquitin modifications from the specific substrate proteins. USP13 gene copy is frequently gained or amplified in more than 80% of human LUSC cases. Although USP13 is one of the most amplified genes in LUSC, yet its role in lung cancer is largely unknown. We established a novel mouse model of LUSC by overexpressing USP13 on KrasG12D/+; Trp53flox/flox background (KPU). KPU-driven lung squamous tumors faithfully recapitulate key pathohistological, molecular features, and cellular pathways of human LUSC. We found that USP13 altered lineage-determining factors in cells of origin in the lung airway and reinforced the cell fate to squamous carcinoma development. We also found a molecular association between USP13 and c-MYC, which may lead to the upregulation of squamous programs in murine and human lung cancer cells. Currently, to understand how USP13 promotes LUSC development, we study the role of USP13 in cancer cell lineage plasticity and mechanistic insight that may have potential implications for treating LUSC.

DEAD-Box RNA Helicases in Non-coding RNAs and Oncoimmunology

An RNA-binding protein, DEAD-Box RNA Helicase 3X (DDX3X) regulates various types of non-coding RNAs, including microRNAs, small RNAs, and long non-coding RNAs. DDX3X regulates cellular endogenous dsRNA homeostasis, and inhibiting DDX3X triggers dsRNA-sensing innate immune signaling in cancers and enhances anti-tumor activity. Aligned with in-depth molecular mechanistic studies, immune-competent syngeneic mouse models, and our unique DDX3X conditional knockout mouse model, we study the molecular mechanism by which DDX3X controls oncogenic or immunogenic cellular non-coding RNAs, and explore the therapeutic implications of targeting DDX3X in cancer.