1. Mechanistically characterized novel ncRNA master regulators for cancer initiation, metastasis, angiogenesis and drug response. Identification of master regulating ncRNAs in cancer and the underlying mechanism is challenging. My lab are capable of integrating the cancer genomics data and experimental validation to identify novel cancer-associated ncRNAs, modeling their down-stream regulatory network, and mechanistically validating their roles using cancer cell line and mouse models. We have functionally characterized seven master miRNAs for ovarian cancer EMT through regulating ZEB2 and SNAI2 (Cancer Cell, 2013). In gastric cancer, we successfully identified a key miRNA regulatory network for cancer metastasis and poor overall survival by targeting ZEB1 (Clinical Cancer Research, 2014 and PNAS, 2015). Our integrated strategy led to the discovery of miR-506 as a novel tumor suppressor in ovarian cancer by regulating EMT (Cancer Cell, 2013), cell senescence (J Pathol, 2014), and HR pathways (JNCI, 2015). Recently, through an integrated analysis of the lncRNA epigenetic landscape in 6475 tumor samples from the TCGA and 781 cancer cell lines from CCLE databases, we have discovered a novel intergenic lncRNA gene, EPIC1, which is overexpressed and associated with poor survival in luminal B breast cancer. My group has cloned and functionally characterized this lncRNA. We have demonstrated that EPIC1 promotes breast cancer tumorigenesis (Cancer Cell, 2018) and MYC inhibitor resistance (Nat Commun, 2018) through directly interacting with MYC protein and enhancing its transcriptional activity.
    • Yang D, Sun Y, Hu L, Zheng H, Ji P, Pecot CV, Zhao Y, Reynolds S, Cheng H, Rupaimoole R, Cogdell D, Nykter M, Broaddus R, Rodriguez-Aguayo C, Lopez-Berestein G, Liu J, Shmulevich I, Sood AK, Chen K, Zhang W. Integrated analyses identify a master microRNA regulatory network for the mesenchymal subtype in serous ovarian cancer. Cancer Cell. 2013 Feb 11;23(2):186-99. PubMed PMID: 23410973; PubMed Central PMCID: PMC3603369.
    • Song F*, Yang D*, Liu B*, Guo Y, Zheng H, Li L, Wang T, Yu J, Zhao Y, Niu R, Liang H, Winkler H, Zhang W, Hao X, Chen K. Integrated microRNA network analyses identify a poor-prognosis subtype of gastric cancer characterized by the miR-200 family. Clin Cancer Res. 2014 Feb 15;20(4):878-89. PubMed PMID: 24352645.
    • Wang Z, Yang B, Zhang M, Guo W, Wu Z, Li S, Lee N, Xie W, Yang D#. LncRNA epigenetic landscape analysis identifies EPIC1 as an oncogenic lncRNA that interacts with MYC and promotes cell cycle progression in cancer, Cancer Cell. 2018 Apr 9;33(4):706-720.e9. PMID: 29622465.
    • Wang Y, Fang Z, Hong M, Yang D#, Xie W#, Long-noncoding RNAs (lncRNAs) in drugmetabolism and disposition, implications incancer chemo-resistance, Acta Pharmaceutica Sinica B, 2020 January, Volume 10, Issue 1, Pages 105-112
  2. Systematically investigated the mechanisms of chemotherapy resistance in cancer. I am among the first researchers to demonstrate that BRCA1 and BRCA2 mutations lead to different genome stabilities and chemotherapy responses in ovarian cancer tumors (JAMA, 2011). My group have successfully characterized a “BRCAness” phenotype in BRCA1/2 wild type ovarian cancer tumors. Further investigation revealed that loss of RAD50 is a driving mechanism for ovarian cancer BRCAness and cisplatin sensitivity (Gynecologic Oncology, 2016). Most recently, we build the first genome-scale data-driven approach for the identification of synthetic viable interactions in cancer genomics, which will help to reveal the mechanism of cancer cell drug resistance (Brief Bioinform, 2017).
    • Wu Z*, Li S*, Tang X, Wang Y, Guo W, Cao G, Chen K, Zhang M#, Guan M#, Yang D#, Copy Number Amplification of DNA Damage Repair Pathways Potentiates Therapeutic Resistance in Cancer. Theranostics. 2020;10(9):3939-3951; PubMed PMID: 32226530; PubMed Central PMCID: PMC7086350.
    • Yang D, Khan S, Sun Y, Hess K, Shmulevich I, Sood AK, Zhang W. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA. 2011 Oct 12;306(14):1557-65. PubMed PMID: 21990299; PubMed Central PMCID: PMC4159096.
    • Zhang M, Liu G, Xue F, Edwards R, Sood A, Zhang, W, Yang D#, Copy number deletion of RAD50 as a predictive marker of BRCAness and PARP inhibitor response in BRCA wild type ovarian cancer, Gynecol Oncol. 2016 Apr;141(1):57-64. PubMed PMID: 27016230; PubMed Central PMCID: PMC4967351.
    • Gu Y, Wang R, Han Y, Zhou W, Zhao Z, Chen T, Zhang Y, Peng F, Liang H, Qi L, Zhao W, Yang D#, Guo Z#, A landscape of synthetic viable interactions in cancer, Brief Bioinform. 2017 Jan 17. pii: bbw142. doi: 10.1093/bib/bbw142. PMID: 28096076
  1. Immunogenomics analysis to delineate tumor microenvironment heterogeneity and chacaterize master regulator of tumor immune evasion. Through whole-exome sequencing tumor clonality analysis, we revealed that drug resistant gastric tumor is characterized by high levels of intra-tumor heterogeneity (PNAS, 2015). Recently, through integrating the lincRNA expression and tumor immune response in 9,626 tumor samples across 32 cancer types, we developed a lincRNA-based immune response (LIMER) score that can predict the immune cell infiltration and patient prognosis in multiple cancer types. By further integrating the lincRNA DNA methylation data, we identified tumor-specific lincRNAs, including EPIC1, that are overexpressed in tumor cells and potentially regulate tumor immune response in multiple cancer types. Immunocompetent mouse models and in vitro co-culture assays demonstrated that EPIC1 induces tumor immune evasion and resistance to immunotherapy by suppressing tumor cell antigen presentation. Mechanistically, lincRNA EPIC1 interacted with the histone methyltransferase EZH2, leading to the epigenetic silencing of IFNGR1, TAP1/2, ERAP1/2, and MHC-I genes. CRISPR knockout and pharmacologically inhibition of EZH2 abolished EPIC1’s immune-related tumorigenic effect and its suppression of IFN-γ-JAK-STAT1 signaling. We propose that the EPIC1-EZH2 axis is as a novel mechanism for tumor immune evasion, which can serve as a therapeutic target for immunotherapy.
    •  Chen K*, Yang D*, Li X*, Sun B, Song F, Cao W, Brat DJ, Gao Z, Li H, Liang H, Zhao Y, Zheng H, Li M, Buckner J, Patterson SD, Ye X, Reinhard C, Bhathena A, Joshi D, Mischel PS, Croce CM, Wang YM, Raghavakaimal S, Li H, Lu X, Pan Y, Chang H, Ba S, Luo L, Cavenee WK, Zhang W, Hao X. Mutational landscape of gastric adenocarcinoma in Chinese: implications for prognosis and therapy. Proc Natl Acad Sci U S A. 2015 Jan 27;112(4):1107-12. PubMed PMID: 25583476; PubMed Central PMCID: PMC4313862.
    • Xu J, Zhao W, Sun J, Huang Y, Wang P, Venkataramanan R, Yang D, Ma X, Rana A and Li S. Novel glucosylceramide synthase inhibitor based prodrug copolymer micelles for delivery of anticancer agents. Journal of Controlled Release 2018; 288212-226.
    • Chen Y, Sun J, Huang Y, Liu Y, Liang L, Yang D, Lu B and Li S. Targeted codelivery of doxorubicin and IL-36gamma expression plasmid for an optimal chemo-gene combination therapy against cancer lung metastasis. Nanomedicine 2019; 15(1): 129-141.
    • Guo, W., Wang, Y., Yang, M., Wang, Z., Wang, Y., Chaurasia, S., Wu, Z., Zhang, M., Yadav, G., Rathod, S., et al., Yang D#. LincRNA-immunity landscape analysis identifies EPIC1 as a regulator of tumor immune evasion by inhibiting IFN-γ-JAK-STAT1 signaling and antigen presentation. Science Advances. (Accepted)
  2. Designed and implemented novel strategy and method to identify “driver” ncRNA genes in cancer initiation and progression. It is conceivable that if some ncRNA genes are repeatedly targeted by somatic chromosome copy number alterations or DNA methylation in cancer samples, these ncRNAs may play an important role in cancer initiation and progression. My group have developed computational algorithms to understand how ncRNA expression is somatically interrupted in the cancer genome and epigenome during tumor initiation and progression. I have led the ncRNA analysis in TCGA colorectal cancer, gastric cancer, low-grade glioma and melanoma working groups to characterize the miRNA regulatory network and subtype by using these methods (Nature , 2012; Cell, 2015; N Engl J Med. 2015). In our most recent study (Nat Commun, 2018), by integrating multiple dimensional pharmacogenomic data of 11,950 lncRNAs in 5,605 tumors and 505 cancer cell lines, we have built lncRNA-drug response models for 265 anti-cancer agents across 27 cancer types. Using Elastic Net (EN) regression model, our analysis identified 27,341 pan-cancer lncRNA-drug predictive pairs. We have shown that cancer cell line based lncRNA EN-models can predict therapeutic outcome in cancer patients. Further lncRNA-pathway co-expression analysis identified ADME chemo-resistance lncRNAs could regulate drug response through drug-metabolism and disposition pathway. These studies lay the foundation of the current project, which aims to mechanistically investigate the role of ADME chemo-resistance lncRNAs in regulation drug metabolism and disposition.
    • Wang Y, Wang Z, Xu J, Li J, Li S, Zhang M, Yang D#. Systematic Identification of Non-coding Pharmacogenomic Landscape in Cancer, Nat Commun, 2018 Aug 9;9(1):3192. doi: 10.1038/s41467-018-05495-9..
    • TCGA Network(including Yang D). Comprehensive molecular characterization of human colon and rectal cancer. 2012 Jul 18;487(7407):330-7. PubMed PMID: 22810696; PubMed Central PMCID: PMC3401966.
    • TCGA Network(including Yang D). Genomic Classification of Cutaneous Melanoma. 2015 Jun 18;161(7):1681-96. PubMed PMID: 26091043; PubMed Central PMCID: PMC4580370.
    • TCGA Network(including Yang D). Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. N Engl J Med. 2015 Jun 25;372(26):2481-98. PubMed PMID: 26061751; PubMed Central PMCID: PMC4530011.

Complete Listing of Publications