Description of Research
My laboratory’s major research efforts focus on the contributions of non-coding RNAs to women’s cancer initiation and progression. Long non-coding RNAs (lncRNAs) are defined as RNA transcripts that contain more than 200 nucleotides and but appear to lack protein-coding potential. ENCODE annotations have recently identified more than 15,900 lncRNA genes within the human genome. These non-coding transcripts can perform multiple functions, including serving as scaffolds or guides to regulate protein-protein or protein-DNA/RNA interactions; as decoys that bind and sequester proteins or miRNAs; or as enhancers that influence gene transcription when transcribed from enhancer regions or their neighboring loci. Indeed, the discovery of lncRNA has dramatically changed our understanding of the biological basis of diseases such as cancer, with recent studies identifying lncRNAs with tumor suppressor or oncogenic promotional activities. However, lncRNA alterations in cancer currently lack systematic characterization. My research program aims to seize these unique opportunities and develop lncRNA research in cancer prevention, diagnosis, and treatment through:
Development of bioinformatic methods and databases for lncRNA studies. We have analyzed lncRNA profiles at the transcriptional, genomic, and epigenetic levels in 5,037 tumor specimens across 13 cancer types from the Cancer Genome Atlas (TCGA) and in 935 cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE). This large-scale, comprehensive analysis revealed that lncRNA alterations are highly tumor- and cell lineage-specific and are often associated with somatic copy number alterations, promoter hypermethylation, and/or cancer risk-SNPs. Importantly, we have developed 2 novel bioinformatics-based methods/strategies for identifying cancer-associated lncRNAs and have explored their biological functions. The first identification strategy is clinically guided, siRNA-based functional screening. This method merges clinical information with lncRNA molecular alteration analytics to generate short lists of candidate lncRNAs and uses biological assays that correspond with clinical outcomes for functional validation. The second strategy for identifying and characterizing lncRNAs involves the analysis of protein coding genes that are co-expressed with lncRNAs to predict the biological function of the lncRNAs. Towards this end, we have developed the Cancer LncRNome Atlas (http://tcla.fcgportal.org/), a publicly accessible resource, to assist researchers with visualizing, analyzing, and downloading multidimensional lncRNome data.
Identification of the cancer driver lncRNA genes. My laboratory has recently identified several novel lncRNAs: Focally Amplified lncRNA on Chromosome 1 (FAL1), Breast Cancer Associated lncRNA 8 (BCAL8), and lncRNA in the NHEJ pathway 1 (LINP1). More specifically, we reported that LINP1 is overexpressed in triple-negative breast cancer. Importantly, LINP1 enhances double-strand DNA break repair by serving as a scaffold that links Ku80 and DNA-PKcs, thereby coordinating the NHEJ pathway. We further discovered that blocking LINP1, which is regulated by the p53 and EGFR signaling, significantly increases breast cancer cell sensitivity to radiotherapy.
Evaluation of lncRNA-based diagnosis and treatments for patients with cancer. The knowledge generated from our basic research findings has been translated into pre-clinical and clinical biomarkers as well as targeted therapy development. We have assembled a team of basic, translational, and clinical research scientists to focus these efforts, with RNA-based serum biomarkers (including miRNA, lncRNA, and exosomal RNA) as subjects of our research focus. In addition, in collaboration with Biotech/Pharma companies focused on RNA-based therapeutics, we have developed a therapeutic strategy that targets oncogenic lncRNAs.
Zhang Y, He Q, HU Z, Feng Y, Fan L, Tang Z, Yuan J, Shan W, Li C, Hu X, Tanyi JL, Fan Y, Huang Q, Montone K, Dang CV, Zhang L: Long noncoding RNA LINP1 regulates repair of DNA double-strand breaks in triple-negative breast cancer. Nat Struct Mol Biol Apr Epub ahead of print, 2016]
Yan X, Hu Z, Feng Yi, Hu X, Yuan J, Zhao SD, Zhang Y, Yang L, Shan W, He Q, Fan L, Kandalaft LE, Tanyi JL, Li C, Yuan C-X, Zhang D, Yuan H, Hua K, Lu Y, Katsaros D, Huang Q, Montone K, Fan Y, Coukos G, Boyd J, Sood AK, Rebbeck T, Mills GB, Dang CV, Zhang L: Comprehensive Genomic Characterization of Long Non-coding RNAs across Human Cancers. Cancer Cell 28(4): 529-40, Oct 2015.
Hu X, Feng Y, Zhang D, Zhao SD, Hu Z, Greshock J, Zhang Y, Yang L, Zhong X, Wang L-P, Jean S, Li C, Huang Q, Katsaros D, Montone KT, Tanyi JL, Lu Y, Boyd J, Nathanson KL, Li H, Mills GB, Zhang L: A Functional Genomic Approach Identifies FAL1 as an Oncogenic Long Noncoding RNA that Associates with BMI1 and Represses p21 Expression in Cancer. Cancer Cell 26(3): 344-57, Sep 2014.
Li N, Kaur S, Greshock J, Lassus H, Zhong X, Wang Y, Leminen A, Shao X, Hu X, Liang S, Katsaros D, Huang Q, Bützow R, Weber BL, Coukos G, Zhang L: A combined array-based comparative genomic hybridization and functional library screening approach identifies mir-30d as an oncomir in cancer. Cancer Res 72(1): 154-64, Jan 2012.
Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang L-P, Gimotty PA, Gilks CB, Lal P, Zhang L, Coukos G: Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 475(7355): 226-30, Jul 2011.
Yang X, Lin X, Zhong X, Kaur S, Li N, Liang S, Lassus H, Wang L, Katsaros D, Montone K, Zhao X, Zhang Y, Bützow R, Coukos G, Zhang L: Double-negative feedback loop between reprogramming factor LIN28 and microRNA let-7 regulates aldehyde dehydrogenase 1-positive cancer stem cells. Cancer Res 70(22): 9463-72, Nov 2010.
Gumireddy K, Li A, Gimotty PA, Klein-Szanto AJ, Showe LC, Katsaros D, Coukos G, Zhang L, Huang Q: KLF17 is a negative regulator of epithelial-mesenchymal transition and metastasis in breast cancer. Nature Cell Biol 11(11): 1297-304, Nov 2009.
Yang N, Kaur S, Volinia S, Greshock J, Lassus H, Hasegawa K, Liang S, Leminen A, Deng S, Smith L, Johnstone CN, Chen X-M, Liu C-G, Huang Q, Katsaros D, Calin GA, Weber BL, Bützow R, Croce CM, Coukos G, Zhang L: MicroRNA microarray identifies Let-7i as a novel biomarker and therapeutic target in human epithelial ovarian cancer. Cancer Res 68(24): 10307-14, Dec 2008.
Zhang L, Huang J, Yang N, Greshock J, Megraw MS, Giannakakis A, Liang S, Naylor TL, Barchetti A, Ward MR, Yao G, Medina A, O'brien-Jenkins A, Katsaros D, Hatzigeorgiou A, Gimotty PA, Weber BL, Coukos G: microRNAs exhibit high frequency genomic alterations in human cancer. Proceed Nat Acad Sciences of USA 103(24): 9136-41, Jun 2006.
Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman M N, Rubin SC, Coukos G: Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. New England Journal of Medicine 348(3): 203-13, Jan 2003.
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Last updated: 06/20/2016
The Trustees of the University of Pennsylvania