Browsing by Author "Wu, Chang-Jiun"

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    An In Vivo Screen Identifies PYGO2 as a Driver for Metastatic Prostate Cancer
    (American Association for Cancer Research, 2018-07-15) Lu, Xin; Pan, Xiaolu; Wu, Chang-Jiun; Zhao, Di; Feng, Shan; Zang, Yong; Lee, Rumi; Khadka, Sunada; Amin, Samirkumar B.; Jin, Eun-Jung; Shang, Xiaoying; Deng, Pingna; Luo, Yanting; Morgenlander, William R.; Weinrich, Jacqueline; Lu, Xuemin; Jiang, Shan; Chang, Qing; Navone, Nora M.; Troncoso, Patricia; DePinho, Ronald A.; Wang, Y. Alan; Biostatistics, IU School of Medicine
    Advanced prostate cancer displays conspicuous chromosomal instability and rampant copy number aberrations, yet the identity of functional drivers resident in many amplicons remain elusive. Here, we implemented a functional genomics approach to identify new oncogenes involved in prostate cancer progression. Through integrated analyses of focal amplicons in large prostate cancer genomic and transcriptomic datasets as well as genes upregulated in metastasis, 276 putative oncogenes were enlisted into an in vivo gain-of-function tumorigenesis screen. Among the top positive hits, we conducted an in-depth functional analysis on Pygopus family PHD finger 2 (PYGO2), located in the amplicon at 1q21.3. PYGO2 overexpression enhances primary tumor growth and local invasion to draining lymph nodes. Conversely, PYGO2 depletion inhibits prostate cancer cell invasion in vitro and progression of primary tumor and metastasis in vivo In clinical samples, PYGO2 upregulation associated with higher Gleason score and metastasis to lymph nodes and bone. Silencing PYGO2 expression in patient-derived xenograft models impairs tumor progression. Finally, PYGO2 is necessary to enhance the transcriptional activation in response to ligand-induced Wnt/β-catenin signaling. Together, our results indicate that PYGO2 functions as a driver oncogene in the 1q21.3 amplicon and may serve as a potential prognostic biomarker and therapeutic target for metastatic prostate cancer.Significance: Amplification/overexpression of PYGO2 may serve as a biomarker for prostate cancer progression and metastasis. Cancer Res; 78(14); 3823-33. ©2018 AACR.
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    Targeting T cell checkpoints 41BB and LAG3 and myeloid cell CXCR1/CXCR2 results in antitumor immunity and durable response in pancreatic cancer
    (Springer Nature, 2023) Gulhati, Pat; Schalck, Aislyn; Jiang, Shan; Shang, Xiaoying; Wu, Chang-Jiun; Hou, Pingping; Hernandez Ruiz, Sharia; Solis Soto, Luisa; Parra, Edwin; Ying, Haoqiang; Han, Jincheng; Dey, Prasenjit; Li, Jun; Deng, Pingna; Sei, Emi; Maeda, Dean Y.; Zebala, John A.; Spring, Denise J.; Kim, Michael; Wang, Huamin; Maitra, Anirban; Moore, Dirk; Clise-Dwyer, Karen; Wang, Y. Alan; Navin, Nicholas E.; DePinho, Ronald A.; Medicine, School of Medicine
    Pancreatic ductal adenocarcinoma (PDAC) is considered non-immunogenic, with trials showing its recalcitrance to PD1 and CTLA4 immune checkpoint therapies (ICTs). Here, we sought to systematically characterize the mechanisms underlying de novo ICT resistance and to identify effective therapeutic options for PDAC. We report that agonist 41BB and antagonist LAG3 ICT alone and in combination, increased survival and antitumor immunity, characterized by modulating T cell subsets with antitumor activity, increased T cell clonality and diversification, decreased immunosuppressive myeloid cells and increased antigen presentation/decreased immunosuppressive capability of myeloid cells. Translational analyses confirmed the expression of 41BB and LAG3 in human PDAC. Since single and dual ICTs were not curative, T cell-activating ICTs were combined with a CXCR1/2 inhibitor targeting immunosuppressive myeloid cells. Triple therapy resulted in durable complete responses. Given similar profiles in human PDAC and the availability of these agents for clinical testing, our findings provide a testable hypothesis for this lethal disease.