Dung-Fang Lee, Ph.D.
- Assistant Professor
- CPRIT Scholar, Cancer Prevention Research Institute of Texas
- Postdoctoral Fellow
- Icahn School of Medicine at Mount Sinai, 2016
- Graduate School of Biomedical Sciences, M.D. Anderson Cancer Center, The University of Texas Health Science Center, Houston, 2008
Areas of Interests
iPSC Disease Modelling, Cancer Pathological Mechanisms
Dissect Cancer Pathogenesis by iPSC Approaches
After leukemia, osteosarcoma is the second leading cause of cancer mortality among children. Genetic alterations (e.g., p53 mutation and RB1 deletion) are strongly associated with osteosarcoma development. Patients with Li-Fraumeni syndrome (LFS), a genetically inherited autosomal dominant cancer disorder caused by germline mutations in the p53 tumor suppressor gene, have increased incidence of osteosarcoma development, which provides a perfect model system to study osteosarcoma.
Modeling human genetic disease has recently become feasible with induced pluripotent stem cell (iPSC) methodologies developed by Dr. Shinya Yamana ka in 2006. Characterized by their ability to self-renew indefinitely and differentiate into all cell lineages of an organism like embryonic stem (ES) cells, iPSCs provide a powerful and unlimited source of cells to generate differentiated cells that can be used to elucidate disease pathogenesis, for drug discovery and development, toxicology screening, personalized healthcare and eventually cell transplantation-based therapies.
Our laboratory is dedicated to understand cancer pathological mechanisms by applying patient-specific iPSCs and/or engineered ESCs. We have established the first human Li-Fraumeni syndrome (LFS) disease model by using LFS patient-specific iPSCs to delineate the pathological mechanisms caused by mutant p53 in osteosarcoma (Lee, et al, Cell 2016). LFS iPSC-derived osteoblasts recapitulate osteosarcoma features including defective osteoblastic differentiation and tumorigenic ability, suggesting that our established LFS disease model is a “disease in a dish” platform for elucidating p53 mutation mediated disease pathogenesis. Since these iPSCs were generated from non-transformed fibroblasts, any recapitulated features of osteosarcoma must be due to the single gene alteration. The patient-specific iPSC model therefore provides a powerful system to elucidate unique gene function in tumor etiology. We continue applying patient-specific iPSCs and TALEN/CRISPR genetically engineered hESCs to illuminate cancer pathological mechanisms.
Current Research projects
- Systems-level analyses and characterization of mutant p53 in LFS-associated osteosarcoma. We will apply TALENs and CRISPR/Cas9 genome editing tools to create p53 mutations in pluripotent stem cells (PSCs; e.g., iPSCs and ESCs). These engineered p53-mutation iPSCs resembling LFS will be differentiated to osteoblasts and their genome-wide alterations examined by transcriptome, miRNA, interactome and ChIP-seq approaches. Integrating these data will provide insights into the tumor suppressor role of p53 in the development of osteosarcoma and elucidate the universal pathological signaling induced by distinct p53 mutations.
- Systematic analyses of genome alterations during LFS-associated osteosarcoma development. LFS patient specific iPSCs-derived cells provide a perfect system to study early genomic alterations and identify the potential second hit required for tumor formation. We will apply genome sequencing to understand dynamic alterations of the genomic landscape of LFS-associated osteosarcoma. The identified second hits represent important therapeutic targets to prevent and treat osteosarcoma in LFS patients.
- Model familial cancer syndrome with predisposition to osteosarcoma by patient-specific iPSC approaches. To explore the common features across multiple genetic osteosarcoma driver mutations, we will establish other osteosarcoma-prone disease models to explore the central pathological mechanisms triggering osteosarcoma development.
- We are also interested in modeling genetic diseases with predisposition to cancers but not limited to osteosarcoma.
- Aguilo F, Zhang F, Sancho A, Fidalgo M, Di Cecilia S, Vashisht A, Lee DF, Chen CH, Rengasamy M, Andino B, Jahouh F, Roman A, Krig SR, Wang R, Zhang W, Wohlschlegel JA, Wang J, Walsh MJ. Coordination of m(6)A mRNA Methylation and Gene Transcription by ZFP217 Regulates Pluripotency and Reprogramming. Cell Stem Cell., 2015 Dec 3;17(6):689-704.
- Mulero-Navarro S, Sevilla A, Roman AC, Lee DF, D’Souza SL, Pardo S, Riess I, Su J, Cohen N, Schaniel C, Rodriguez NA, Baccarini A, Brown BD, Cavé H, Caye A, Strullu M, Yalcin S, Park CY, Dhandapany PS, Yongchao G, Edelmann L, Bahieg S, Raynal P, Flex E, Tartaglia M, Moore KA, Lemischka IR, Gelb BD. Myeloid Dysregulation in a Human Induced Pluripotent Stem Cell Model of PTPN11-Associated Juvenile Myelomonocytic Leukemia. Cell Rep., 2015 Oct 20;13(3):504-15.
- Gingold JA, Coakley ES, Su J, Lee DF, Lau Z, Zhou H, Felsenfeld DP, Schaniel C, Lemischka IR. Distribution Analyzer, a methodology for identifying and clustering outlier conditions from single-cell distributions, and its application to Nanog reporter RNAi screen. BMC Bioinformatics, 2015 Jul 22;16:225.
- Waghray A, Saiz N, Jayaprakash AD, Freire AG, Papatsenko D, Pereira CF, Lee DF, Brosh R, Chang B, Darr H, Gingold J, Kelley K, Schaniel C, Hadjantonakis AK, Lemischka IR. Tbx3 Controls Dappa3 Levels and Exit from Pluripotency toward Mesoderm. Stem Cell Reports, 2015 Jul 14;5(1):97-110.
- Ding J, Huang X, Shao N, Zhou H, Lee DF, Faiola F, Fidalgo M, Guallar D, Saunders A, Shliaha PV, Wang H, Waghray A, Papatsenko D, Sánchez-Priego C, Li D, Yuan Y, Lemischka IR, Shen L, Kelley K, Deng H, Shen X, Wang J. Tex10 Coordinates Epigenetic Control of Super-Enhancer Activity in Pluripotency and Reprogramming. Cell Stem Cell. 2015 Jun 4;16(6):653-68.
- Lee DF, Su J, Kim HS, Chang B, Papatsenko D, Zhao R, Ye Yuan, Gingold J, Xia W, Darr H, Mirzayans R, Hung MC, Schaniel C, Lemischka IR. Modeling Familial Cancer with Induced Pluripotent Stem Cells. Cell., 2015 Apr 9;161(2):240-54.
*Cell Video Abstract: Modeling Cancer with Stem Cells (https://www.youtube.com/watch?v=88cl5Fpg6OI)
* Recommended in F1000 Prime (http://f1000.com/prime/725429874)
- Huo L, Li CW, Huang TH, Lam YC, Xia W, Tu C, Chang WC, Hsu JL, Lee DF, Nie L, Yamaguchi H, Wang Y, Lang J, Li LY, Chen CH, Mishra L, Hung MC. Activation of Keap1/Nrf2 signaling pathway by nuclear epidermal growth factor receptor in cancer cells. Am J Transl Res., 2014 Nov 22;6(6):649-63.
- Gingold JA, Fidalgo M, Guallar D, Lau Z, Sun Z, Zhou H, Faiola F, Huang X, Lee DF, Waghray A, Schaniel C, Felsenfeld DP, Lemischka IR, Wang J. A genome-wide RNAi screen identifies opposing functions of Snail1 and Snail2 on the Nanog dependency of establishing pluripotency. Mol Cell., 2014 Oct 2;56(1):140-52.
- Kim HS, Bernitz J, Lee DF, Lemischka IR. Genomic editing tools to model human disease with isogenic pluripotent stem cells. Stem Cells Dev., 2014 Nov 15;23(22):2673-86.
- Kuo HP, Wang Z, Lee DF, Iwasaki M, Duque-Afonso J, Wong SH, Lin CH, Figueroa ME, Su J, Lemischka IR, Cleary ML. Epigenetic roles of MLL oncoproteins are dependent on NF-κB. Cancer Cell., 2013 Oct 14;24(4):423-37.
- Lee DF, Su J, Ang YS, Carvajal-Vergara X, Mulero-Navarro S, Pereira CF, Gingold J, Wang HL, Zhao R, Sevilla A, Darr H, Williamson AJ, Chang B, Niu X, Aguilo F, Flores ER, Sher YP, Hung MC, Whetton AD, Gelb BD, Moore KA, Snoeck HW, Ma’ayan A, Schaniel C, Lemischka IR. Regulation of Embryonic and Induced Pluripotency by Aurora Kinase-p53 Signaling. Cell Stem Cell., 2012 Aug 3;11(2):179-94. * Featured in 2012 October Issue of Nature Cell Biology Research Highlights “Aurora A maintains embryonic stem cells” p990.
- Lee DF, Su J, Sevilla A, Gingold J, Schaniel C, Lemischka IR. Combining competition assays with genetic complementation strategies to dissect mouse embryonic stem cell self-renewal and pluripotency. Nat Protocols., 2012 Mar 22;7(4):729-48.
- Wang Y, Ding QQ, Yen CJ, Xia W, Izzo JG, Lang JY, Li CW, Miller SA, Wang X, Lee DF, Hsu JL, Hsu JM, Huo LF, LaBaff AM, Liu DP, Huang TH, Lai CC, Tsai FU, Chang WC, Chen CH, Wu TT, Buttar NS, Wang KK, Wu Y, Wang H, Ajani J, Hung MC. The crosstalk of mTOR/S6K1 and Hedgehog pathways. Cancer Cell., 2012 Mar 20;21(3):374-87.
- Ling J, Kang Y, Zhao R, Xia Q, Lee DF, Chang Z, Peng B, Fleming JB, Wang H, Lemischka IR, Hung MC, Chiao PJ. KrasG12D-Induced IKK2/beta/NF-kappaB Activation by IL-1alpha and p62 Feedforward Loops is Required for Development of Pancreatic Ductal Adenocarcinoma. Cancer Cell., 2012 Jan 17;21(1):105-20.
- Liu M, Lee DF, Chen CT, Yen CJ, Li LY, Lee HJ, Chang CJ, Chang WC, Hsu JM, Kuo HP, Xia W, Wei Y, Chiu PC, Chou CK, Du Y, Dhar D, Karin M, Chen CH, Hung MC. IKKα activation of NOTCH links tumorigenesis via FOXA2 suppression. Mol Cell., 2012 Jan 27;45(2):171-84.
- Ding Q, Chang CJ, Xie X, Xia W, Yang JY, Wang SC, Wang Y, Xia J, Chen L, Cai C, Li H, Yen CJ, Kuo HP, Lee DF, Lang J, Huo L, Cheng X, Chen YJ, Li CW, Jeng LB, Hsu JL, Li LY, Tan A, Curley SA, Ellis LM, Dubois RN, Hung MC. APOBEC3G promotes liver metastasis in an orthotopic mouse model of colorectal cancer and predicts human hepatic metastasis. J Clin Invest., 2011 Nov;121(11):4526-36.
- Su JL, Cheng X, Yamaguchi H, Chang YW, Hou CF, Lee DF, Ko HW, Hua KT, Wang YN, Hsiao M, Chen PB, Hsu JM, Bast RC Jr, Hortobagyi GN, Hung MC. FOXO3a dependent mechanism of E1A-induced chemosensitization. Cancer Res., 2011 Nov 1;71(21):6878-87.
- Li C, Ao J, Fu J, Lee DF, Xu J, Lonard D, O’Malley BW. Tumor-suppressor role for the SPOP ubiquitin ligase in signal-dependent proteolysis of the oncogenic co-activator SRC-3/AIB1. Oncogene., 2011 Oct 20;30(42):4350-64.
- Zhang X, Yalcin S, Lee DF, Yeh TY, Lee SM, Su J, Mungamuri SK, Pimmele P, Kennedy M, Sellers R, Landthaler M, Tuschl T, Chi NW, Lemischka I, Keller G, Ghaffari S. FOXO1 is an essential regulator of pluripotency in human embryonic stem cells. Nat Cell Biol., 2011 Jul 31;13(9):1092-9.
- Tsai SY, Bouwman BA, Ang YS, Kim SJ, Lee DF, Lemischka IR, Rendl M. Single transcription factor reprogramming of hair follicle dermal papilla cells to induced pluripotent stem cells. Stem Cells., 2011 Jun;29(6):964-71.
- Ang YS, Tsai SY, Lee DF, Monk J, Su J, Ratnakumar K, Ding J, Ge Y, Darr H, Chang B, Wang J, Rendl M, Bernstein E, Schaniel C, Lemischka IR. Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network. Cell., 2011 Apr 15;145(2):183-97. * Recommended in F1000 Prime (http://f1000.com/prime/10081956.)
- Aguilo F, Avagyan S, Labar AS, Sevilla A, Lee DF, Kumar P, Lemischka IR, Zhou BY, Snoeck HW. Prdm16 is physiological regulator of hematopoietic stem cells. Blood., 2011 May 12; 117(9):5057-66.
- Zhao R, Yeung SC, Chen J, Iwakuma T, Su CH, Chen B, Qu C, Zhang F, Chen YT, Lin YL, Lee DF, Jin F, Zhu R, Shaikenov T, Sarbassov D, Sahin A, Wang H, Wang H, Lai CC, Tsai FJ, Lozano G, Lee MH. Subunit 6 of the COP9 signalosome promotes tumorigenesis in mice through stabilization of MDM2 and is upregulated in human cancer. J Clin Invest., 2011 Mar 1;121(3):851-65.