Browsing by Author "Wang, Y. Alan"

Now showing 1 - 8 of 8
  • Thumbnail Image
    Item
    Effective combinatorial immunotherapy for penile squamous cell carcinoma
    (Springer Nature, 2020-05-01) Huang, Tianhe; Cheng, Xi; Chahoud, Jad; Sarhan, Ahmed; Tamboli, Pheroze; Rao, Priya; Guo, Ming; Manyam, Ganiraju; Zhang, Li; Xiang, Yu; Han, Leng; Shang, Xiaoying; Deng, Pingna; Luo, Yanting; Lu, Xuemin; Feng, Shan; Ferrer, Magaly Martinez; Wang, Y. Alan; DePinho, Ronald A.; Pettaway, Curtis A.; Lu, Xin; Medicine, School of Medicine
    Penile squamous cell carcinoma (PSCC) accounts for over 95% of penile malignancies and causes significant mortality and morbidity in developing countries. Molecular mechanisms and therapies of PSCC are understudied, owing to scarcity of laboratory models. Herein, we describe a genetically engineered mouse model of PSCC, by co-deletion of Smad4 and Apc in the androgen-responsive epithelium of the penis. Mouse PSCC fosters an immunosuppressive microenvironment with myeloid-derived suppressor cells (MDSCs) as a dominant population. Preclinical trials in the model demonstrate synergistic efficacy of immune checkpoint blockade with the MDSC-diminishing drugs cabozantinib or celecoxib. A critical clinical problem of PSCC is chemoresistance to cisplatin, which is induced by Pten deficiency on the backdrop of Smad4/Apc co-deletion. Drug screen studies informed by targeted proteomics identify a few potential therapeutic strategies for PSCC. Our studies have established what we believe to be essential resources for studying PSCC biology and developing therapeutic strategies.
  • Thumbnail Image
    Item
    Gastric cancer immunosuppressive microenvironment heterogeneity: implications for therapy development
    (Elsevier, 2024) Yasuda, Tadahito; Wang, Y. Alan; Medicine, School of Medicine
    Although immunotherapy has revolutionized solid tumor treatment, durable responses in gastric cancer (GC) remain limited. The heterogeneous tumor microenvironment (TME) facilitates immune evasion, contributing to resistance to conventional and immune therapies. Recent studies have highlighted how specific TME components in GC acquire immune escape capabilities through cancer-specific factors. Understanding the underlying molecular mechanisms and targeting the immunosuppressive TME will enhance immunotherapy efficacy and patient outcomes. This review summarizes recent advances in GC TME research and explores the role of the immune-suppressive system as a context-specific determinant. We also provide insights into potential treatments beyond checkpoint inhibition.
  • Thumbnail Image
    Item
    Glioblastoma heterogeneity at single cell resolution
    (Springer Nature, 2023) Eisenbarth, David; Wang, Y. Alan; Medicine, School of Medicine
    Glioblastoma (GBM) is one of the deadliest types of cancer and highly refractory to chemoradiation and immunotherapy. One of the main reasons for this resistance to therapy lies within the heterogeneity of the tumor and its associated microenvironment. The vast diversity of cell states, composition of cells, and phenotypical characteristics makes it difficult to accurately classify GBM into distinct subtypes and find effective therapies. The advancement of sequencing technologies in recent years has further corroborated the heterogeneity of GBM at the single cell level. Recent studies have only begun to elucidate the different cell states present in GBM and how they correlate with sensitivity to therapy. Furthermore, it has become clear that GBM heterogeneity not only depends on intrinsic factors but also strongly differs between new and recurrent GBM, and treatment naïve and experienced patients. Understanding and connecting the complex cellular network that underlies GBM heterogeneity will be indispensable in finding new ways to tackle this deadly disease. Here, we present an overview of the multiple layers of GBM heterogeneity and discuss novel findings in the age of single cell technologies.
  • Thumbnail Image
    Item
    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.
  • Thumbnail Image
    Item
    Opposing roles of TGFβ and BMP signaling in prostate cancer development
    (Cold Spring Harbor Laboratory Press, 2017-12-01) Lu, Xin; Jin, Eun-Jung; Cheng, Xi; Feng, Shan; Shang, Xiaoying; Deng, Pingna; Jiang, Shan; Chang, Qing; Rahmy, Sharif; Chaudhary, Seema; Lu, Xuemin; Zhao, Ren; Wang, Y. Alan; DePinho, Ronald A.; Medicine, School of Medicine
    SMAD4 constrains progression of Pten-null prostate cancer and serves as a common downstream node of transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) pathways. Here, we dissected the roles of TGFβ receptor II (TGFBR2) and BMP receptor II (BMPR2) using a Pten-null prostate cancer model. These studies demonstrated that the molecular actions of TGFBR2 result in both SMAD4-dependent constraint of proliferation and SMAD4-independent activation of apoptosis. In contrast, BMPR2 deletion extended survival relative to Pten deletion alone, establishing its promoting role in BMP6-driven prostate cancer progression. These analyses reveal the complexity of TGFβ-BMP signaling and illuminate potential therapeutic targets for prostate cancer.
  • Thumbnail Image
    Item
    SUV39H1 maintains cancer stem cell chromatin state and properties in glioblastoma
    (American Society for Clinical Investigation, 2025-03-10) Li, Chunying; Xie, Qiqi; Ghosh, Sugata; Cao, Bihui; Du, Yuanning; Vo, Giau V.; Huang, Timothy Y.; Spruck, Charles; Carpenter, Richard L.; Wang, Y. Alan; Lu, Q. Richard; Nephew, Kenneth P.; Shen, Jia; Biochemistry and Molecular Biology, School of Medicine
    Glioblastoma (GBM) is the most lethal brain cancer, with GBM stem cells (GSCs) driving therapeutic resistance and recurrence. Targeting GSCs offers a promising strategy for preventing tumor relapse and improving outcomes. We identify SUV39H1, a histone-3, lysine-9 methyltransferase, as critical for GSC maintenance and GBM progression. SUV39H1 is upregulated in GBM compared with normal brain tissues, with single-cell RNA-seq showing its expression predominantly in GSCs due to super-enhancer-mediated activation. Knockdown of SUV39H1 in GSCs impaired their proliferation and stemness. Whole-cell RNA-seq analysis revealed that SUV39H1 regulates G2/M cell cycle progression, stem cell maintenance, and cell death pathways in GSCs. By integrating the RNA-seq data with ATAC-seq data, we further demonstrated that knockdown of SUV39H1 altered chromatin accessibility in key genes associated with these pathways. Chaetocin, an SUV39H1 inhibitor, mimics the effects of SUV39H1 knockdown, reducing GSC stemness and sensitizing cells to temozolomide, a standard GBM chemotherapy. In a patient-derived xenograft model, targeting SUV39H1 inhibits GSC-driven tumor growth. Clinically, high SUV39H1 expression correlates with poor glioma prognosis, supporting its relevance as a therapeutic target. This study identifies SUV39H1 as a crucial regulator of GSC maintenance and a promising therapeutic target to improve GBM treatment and patient outcomes.
  • Thumbnail Image
    Item
    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.
  • Thumbnail Image
    Item
    USP14 promotes tryptophan metabolism and immune suppression by stabilizing IDO1 in colorectal cancer
    (Springer Nature, 2022-09-26) Shi, Dongni; Wu, Xianqiu; Jian, Yunting; Wang, Junye; Huang, Chengmei; Mo, Shuang; Li, Yue; Li, Fengtian; Zhang, Chao; Zhang, Dongsheng; Zhang, Huizhong; Huang, Huilin; Chen, Xin; Wang, Y. Alan; Lin, Chuyong; Liu, Guozhen; Song, Libing; Liao, Wenting; Medicine, School of Medicine
    Indoleamine 2,3 dioxygenase 1 (IDO1) is an attractive target for cancer immunotherapy. However, IDO1 inhibitors have shown disappointing therapeutic efficacy in clinical trials, mainly because of the activation of the aryl hydrocarbon receptor (AhR). Here, we show a post-transcriptional regulatory mechanism of IDO1 regulated by a proteasome-associated deubiquitinating enzyme, USP14, in colorectal cancer (CRC). Overexpression of USP14 promotes tryptophan metabolism and T-cell dysfunction by stabilizing the IDO1 protein. Knockdown of USP14 or pharmacological targeting of USP14 decreases IDO1 expression, reverses suppression of cytotoxic T cells, and increases responsiveness to anti-PD-1 in a MC38 syngeneic mouse model. Importantly, suppression of USP14 has no effects on AhR activation induced by the IDO1 inhibitor. These findings highlight a relevant role of USP14 in post-translational regulation of IDO1 and in the suppression of antitumor immunity, suggesting that inhibition of USP14 may represent a promising strategy for CRC immunotherapy.