Browsing by Author "Han, Cecil"

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    Targeting 17q23 amplicon to overcome the resistance to anti-HER2 therapy in HER2+ breast cancer
    (Nature Research, 2018-11-09) Liu, Yunhua; Xu, Jiangsheng; Choi, Hyun Ho; Han, Cecil; Fang, Yuanzhang; Li, Yujing; Van der Jeught, Kevin; Xu, Hanchen; Zhang, Lu; Frieden, Michael; Wang, Lifei; Eyvani, Haniyeh; Sun, Yifan; Zhao, Gang; Zhang, Yuntian; Liu, Sheng; Wan, Jun; Huang, Cheng; Ji, Guang; Lu, Xiongbin; He, Xiaoming; Zhang, Xinna; Medical and Molecular Genetics, School of Medicine
    Chromosome 17q23 amplification occurs in ~11% of human breast cancers. Enriched in HER2+ breast cancers, the 17q23 amplification is significantly correlated with poor clinical outcomes. In addition to the previously identified oncogene WIP1, we uncover an oncogenic microRNA gene, MIR21, in a majority of the WIP1-containing 17q23 amplicons. The 17q23 amplification results in aberrant expression of WIP1 and miR-21, which not only promotes breast tumorigenesis, but also leads to resistance to anti-HER2 therapies. Inhibiting WIP1 and miR-21 selectively inhibits the proliferation, survival and tumorigenic potential of the HER2+ breast cancer cells harboring 17q23 amplification. To overcome the resistance of trastuzumab-based therapies in vivo, we develop pH-sensitive nanoparticles for specific co-delivery of the WIP1 and miR-21 inhibitors into HER2+ breast tumors, leading to a profound reduction of tumor growth. These results demonstrate the great potential of the combined treatment of WIP1 and miR-21 inhibitors for the trastuzumab-resistant HER2+ breast cancers.
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    Targeting DDX3X Triggers Antitumor Immunity via a dsRNA-Mediated Tumor-Intrinsic Type I Interferon Response
    (American Association for Cancer Research, 2021) Choi, Hyeongjwa; Kwon, Juntae; Cho, Min Soon; Sun, Yifan; Zheng, Xiaofeng; Wang, Jing; Bouker, Kerrie B.; Casey, John L.; Atkins, Michael B.; Toretsky, Jeffrey; Han, Cecil; Medical and Molecular Genetics, School of Medicine
    Induction of nucleic-acid sensing-mediated type I interferon (IFN) has emerged as a novel approach to activate the immune system against cancer. Here we show that the depletion of DEAD-box RNA helicase 3X (DDX3X) triggers a tumor-intrinsic type I IFN response in breast cancer cells. Depletion or inhibition of DDX3X activity led to aberrant cytoplasmic accumulation of cellular endogenous double-stranded RNAs (dsRNA), which triggered type I IFN production through the melanoma differentiation-associated gene 5 (MDA5)-mediated dsRNA sensing pathway. Furthermore, DDX3X interacted with dsRNA-editing ADAR1 and dual depletion of DDX3X and ADAR1 synergistically activated the cytosolic dsRNA pathway in breast cancer cells. Loss of DDX3X in mouse mammary tumors enhanced anti-tumor activity by increasing the tumor-intrinsic type I IFN response, antigen presentation, and tumor-infiltration of cytotoxic T and dendritic cells. These findings may lead to the development of a novel therapeutic approach for breast cancer by targeting DDX3X in combination with immune checkpoint blockade.
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    USP13 promotes development and metastasis of high-grade serous ovarian carcinoma in a novel mouse model
    (Springer Nature, 2022) Kwon, Juntae; Choi, Hyeongjwa; Ware, Anna D.; Morillo, Bernadette Cecilia; Wang, Haiyang; Bouker, Kerrie B.; Lu, Xiongbin; Waldman, Todd; Han, Cecil; Medical and Molecular Genetics, School of Medicine
    Epithelial ovarian cancer is the most lethal gynecologic malignancy and one of the most common causes of cancer mortality among women worldwide. Ubiquitin-Specific Peptidase 13 (USP13) gene copy is strongly amplified in human epithelial ovarian cancer, and high USP13 expression is correlated with poor survival outcomes. Yet, its pathological contribution to ovarian tumorigenesis remains unknown. We crossed a conditional Usp13 overexpressing knock-in mouse with a conditional knockout of Trp53 and Pten mouse and generated a novel ovarian cancer genetically engineered mouse model (GEMM), which closely recapitulates the genetic changes driving ovarian cancer in humans. Overexpression of USP13 with deletion of Trp53 and Pten in murine ovarian surface epithelium accelerated ovarian tumorigenesis and led to decreased survival in mice. Notably, USP13 greatly enhanced peritoneal metastasis of ovarian tumors with frequent development of hemorrhagic ascites. The primary and metastatic tumors exhibited morphology and clinical behavior similar to human high-grade serous ovarian cancer. Co-inhibition of USP13 and AKT significantly decreased the viability of the primary murine ovarian cancer cells isolated from the GEMM. USP13 also increased the tumorigenic and metastatic abilities of primary murine ovarian cancer cells in a syngeneic mouse study. These findings suggest a critical role of USP13 in ovarian cancer development and reveal USP13 as a potential therapeutic target for ovarian cancer.