Lin Zhang, M.D.

faculty photo
Harry Fields Research Professor
Department: Obstetrics and Gynecology

Contact information
University of Pennsylvania School of Medicine
421 Curie Blvd, Biomedical Research Building II/III
Lab: 1233~1237; Office: 1207
linzhang@mail.med.upenn.edu
Philadelphia, PA 19104
Office: 215-573-4780
Fax: 215-573-7627
Lab: 215-573-7947
Education:
MD
China Medical University, 1996.
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Description of Research Expertise

Our research efforts have been focused on the characterization of molecular mechanisms and the development of novel therapies for cancer by a combination of computational and molecular biology approaches. We reported that long non-coding RNAs exhibit genomic alterations with high frequency in cancer (Cancer Cell 2014, and Cancer Cell 2015). We developed novel strategies to target DNA repair pathways in combination with inhibition of certain long non-coding RNA or epigenetic regulators to treat breast and ovarian cancer (Nature Structural and Molecular Biology 2016, Science Translational Medicine 2017, and Cell Reports 2020). Recently, by integrating large-scale and multi-dimensional genomic profiles, we developed a Functional Cancer Genome data portal (FCG data portal: http://52.25.87.215/home/) to functionally annotate TCGA genomic profiles. Examples include annotations on the relationship between genetic ancestry and genomic alteration (Cancer Cell 2018) and genomic alterations in epigenetic regulatory genes (Nature Communications 2019). Our early and still ongoing research is directed towards investigating the antitumor immune response and developing immunotherapy strategies for ovarian cancer. Our studies provided strong clinical evidence to support the concept of immune surveillance in ovarian cancer (New England Journal of Medicine 2003).

1. Noncoding RNAs in epigenetic regulation and DNA damage response.
We comprehensively characterized long noncoding RNA dysregulation in a large sample cohort. Our multidimensional genomic analysis revealed that long noncoding RNA alterations are associated with somatic copy number changes, promoter hypermethylation, and cancer risk-associated SNPs. Using a genomic guided genetic screening approach, our laboratory has identified several cancer-associated noncoding RNAs and extensively investigated their functions in epigenetic regulation and the DNA damage response.

2. Functional characterization of the cancer genomes.
Through a combination of multiple computational algorithms, we developed a systems biology approach to integrate multi-dimensional and large-scale genomic profiles. A publicly accessible database, the Functional Cancer Genome data portal (FCG data portal), has been developed by our laboratory. To assist researchers with analyzing and visualizing TCGA genomic data, multiple genomic data sets have been released via our FCG data portal (FCG data portal: http://52.25.87.215/home/), including the Cancer LncRNome Atlas (TCLA), and the Cancer Genetic Ancestry Atlas (TCGAA).

3. Immunotherapy and targeted therapy for women’s cancer.
Our early and still ongoing research focuses on characterizing the antitumor immune response and on developing new immunotherapy strategies for patients with ovarian cancer. We investigated the correlation between T lymphocyte infiltration and patient survival, providing strong evidence to support the concept of immune surveillance. Recently, using a computational biology approach, our laboratory functionally characterized genomic alterations of the druggable genes, such as epigenetic regulatory genes, across multiple cancer types. We identified novel therapeutic targets and drug combination strategies. For example, we provided rationale for the clinical application of BET inhibitor in combination with PARP inhibitor for cancer treatment.

4. Genomic alterations of microRNA genes in cancer.
We provided experimental documentation of genome-wide microRNA copy number alterations in cancer. Our laboratory has extensively investigated microRNA-based diagnosis and treatment strategies for patients with cancer. We reported that microRNA expression signatures are informative for cancer diagnosis, prognosis, classification, and clinical prediction, and that selected microRNAs can serve as therapeutic targets for cancer treatment.

5. The heterochronic pathway in embryonic stem cell differentiation and cancer development.
We showed strong connections between the heterochronic pathway and tumorigenesis in ovarian and breast cancers. Heterochrony describes the phylogenetic variation in the relative timing of major developmental events between related species. Our laboratory reported that LIN28 promotes tumorigenesis by regulating differentiation and controlling the cell cycle. A nanoparticle-based let-7 replacement therapy has recently been developed in our laboratory.

Selected Publications

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.

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.

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.

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 23(6):522-30, Apr 2016.

Yang L, Zhang Y, Shan W, Hu Z, Yuan J, Pi J, Wang Y, Fan L, Tang Z, Li C, Hu X, Tanyi JL, Fan Y, Huang Q, Montone K, Dang CV, Zhang L: Repression of BET activity sensitizes homologous recombination-proficient cancers to PARP inhibition. Sci Transl Med 26:9(400), Jul 2017.

Yuan J, Hu Z, Mahal B, Zhao S, Kensler K, Pi J, Hu X, Wang Y, Jiang J, Zhang Y, Li C, Zhong X, Montone K, Guan G, Tanyi J, Fan Y, Xu X, Long M, Morgan M, Zhang Y, Zhang R, Sood A, Rebbeck T, Dang C, Zhang L.: Integrated analysis of genetic ancestry and genomic alterations across cancers. Cancer Cell 34(4):549-560.e9., 2018.

Zhongyi Hu, Junzhi Zhou, Junjie Jiang, Jiao Yuan, Youyou Zhang, Xuepeng Wei, Nicki Loo, Yueying Wang, Yutian Pan, Tianli Zhang, Xiaomin Zhong, Meixiao Long, Kathleen Montone, Janos Tanyi, Yi Fan, Tian-Li Wang, Ie-Ming Shih, Xiaowen Hu, Lin Zhang: Genomic characterization of genes encoding histone acetylation modulator proteins identifies therapeutic targets for cancer treatment. Nature Communications Page: Feb 13;10(1):733. doi: 10.1038/s41467-019-08554-x. 2019.

Shan W, Yuan J, Hu J, Jiang J, Wang Y, Loo N, Fan L, Tang Z, Zhang T, Xu M, Pan Y, Lu J, Long M, Tanyi LJ, Montone KT, Fan Y, Hu X, Zhang Y, Zhang L.: Systematic characterization of recurrent genomic alterations in cyclin-dependent kinases reveals potential therapeutic strategies for cancer treatment. Cell Reports 32 (2), 107884, 2020.

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Last updated: 08/31/2020
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