- 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 Interest
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.
- Chachad D, Patel LR, Recio CV, Pourebrahim R, Whitley EM, Wang W, Su X, Xu A, Lee DF, Lozano G. (2023). Unique transcriptional profiles underlie osteosarcomagenesis driven by different p53 mutants. Cancer Res. Jul 14;83(14):2297-2311.
- Choe JH, Kawase T, Xu A, Guzman A, Tong DR, Obraadovic AZ, Low-Calle AM, Alaghebandan B, Raghavan A, Long K, Hwang PM, Schiffman JD, Zhu Y, Zhao R, Lee DF*, Katz C*, Prives C*. (2023). Li-Fraumeni Syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death. Cancer Discov. May 4;13(5):1250-1273. (*corresponding author) #Commentary by Stieg et al., Cancer Discov. May 4;13(5):1046-1048.
- Xu A, Liu M, Hung MF, Zhang Y, Hu R, Gingold JA, Liu Y, Zhu D, Chien CS, Wang WC, Liao Z, Yuan F, Hsu CW, Tu J, Yu Y, Rosen T, Xiong F, Jia P, Yang YP, Bazer DA, Chen YW, Li W, Huff CD, Zhu JJ, Aguilo F, Chiou SH, Boles NC, Lai CC, Hung MC, Zhao Z, Van Nostrand EL, Zhao R*, Lee DF*. (2023). Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation. Nat Commun. Mar 27;14(1):1694. (*corresponding author) #Featured Article by Nat Commun Editor Dr. Stephanie Koo
- Lee DF, Pereira CF. (2023). Reprogramming Stars #10: Modeling Cancer with Cellular Reprogramming-An Interview with Dr. Dung-Fang Lee. Cell Reprogram. Jan 31.
- Huang MF, Shoemaker R, Lee DF. (2022). Bcl11b and Atoh8 Coordinate Cellular Plasticity for Reprogramming and Transformation. Cell Reprogram. Dec;24(6):324-326.
- LK Pang, MF Huang, JA Gingold, M Pena, R Zhao, DF Lee. (2022). Progress and possibilities for patient-derived iPSCs and genetically engineered stem cells in cancer modeling and targeted therapies. IPSCs-State of the Science 16, 247-288.
- Li HB, Huang G, Tu J, Lv DM, Jin QL, Chen JK, Zou YT, Lee DF, Xie D, Shen JN, Xie XB. (2022). METTL14-mediated epitranscriptome modification of MN1 mRNA promotes tumorigenicity and all-trans-retinoic acid resistance in osteosarcoma. EBioMedicine. Jul 7;82:104142.
- Tu J, Huo Z, Yu Y, Zhu D, Xu A, Huang MF, Hu R, Wang R, Gingold JA, Chen YH, Tsai KL, Forcioli-Conti NR, Huang SXL, Webb TR, Su J, Bazer DA, Jia P, Yustein JT, Wang LL, Hung MC, Zhao Z, Huff CD, Shen J, Zhao R*, Lee DF*. (2022). Hereditary retinoblastoma iPSC model reveals aberrant spliceosome function driving bone malignancies. Proc Natl Acad Sci U S A. Apr 19;119(16):e2117857119. (*corresponding author)
- Malla S, Prasad Bhattarai D, Groza P, Melguizo-Sanchis D, Atanasoai I, Martinez-Gamero C, Román ÁC, Zhu D, Lee DF, Kutter C, Aguilo F.,(2022). ZFP207 sustains pluripotency by coordinating OCT4 stability, alternative splicing and RNA export. EMBO Rep. Jan 17:e53191.
- Jewell BE, Xu A, Zhu D, Huang MF, Lu L, Liu M, Underwood EL, Park JH, Gingold JA, Zhou R, Tu J, Huo Z, Liu Y, Jin W, Chen YH, Xu Y, Chen SH, Rainusso N, Berg NK, Bazer DA, Vellano C, Jones P, Eltzschig HK, Kaipparettu BA, Zhao R, Wang LL*, Lee DF*. (2021). Patient-derived iPSCs Link Elevated Mitochondrial Respiratory Complex I Function to Osteosarcoma in Rothmund-Thomson Syndrome. PLoS Genet. Dec 29;17(12):e1009971. (*corresponding author)
- Huang MF, Pang LK, Chen YH, Zhao R, Lee DF. (2021). Cardiotoxicity of Antineoplastic Therapies and Applications of Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Cells. Oct 21;10(11):2823.
- Chiang YT, Chien YC, Lin YH, Wu HH, Lee DF, Yu YL. (2021). The Function of the Mutant p53-R175H in Cancer. Cancers (Basel). Aug 13;13(16):4088.
- Huang PS, Wen MH, Xie X, Xu A, Lee DF, Chen TY. (2021). Generation of a homozygous knock-in human embryonic stem cell line expressing SNAP-tagged SOD1. Stem Cell Res. Jul;54:102415.
- Xiong F, Wang R, Lee JH, Li S, Chen SF, Liao Z, Hasani LA, Nguyen PT, Zhu X, Krakowiak J, Lee DF, Han L, Tsai KL, Liu Y, Li W. (2021). RNA m6A modification orchestrates a LINE-1-host interaction that facilitates retrotransposition and contributes to long gene vulnerability. Cell Res. Aug;31(8):861-885.
- Sevilla A, Papatsenko D, Mazloom AR, Xu H, Vasileva A, Unwin RD, LeRoy G, Chen EY, Garrett-Bakelman FE, Lee DF, Trinite B, Webb RL, Wang Z, Su J, Gingold J, Melnick A, Garcia BA, Whetton AD, MacArthur BD, Ma’ayan A, Lemischka IR. (2021). An Esrrb and Nanog Cell Fate Regulatory Module Controlled by Feed Forward Loop Interactions. Front Cell Dev Biol. Mar 19;9:630067.
- Papapetrou EP, Lee DF. (2021). Reprogramming and cancer. Stem Cell Res. Apr;52:102249.
- Xu A, Huang MF, Zhu D, Gingold JA, Bazer DA, Chang B, Wang D, Lai CC, Lemischka IR, Zhao R, Lee DF. (2021). LncRNA H19 Suppresses Osteosarcomagenesis by Regulating snoRNAs and DNA Repair Protein Complexes. Front Genet. Jan 15;11:611823.
- Pang LK, Pena M, Zhao R, Lee DF. (2020). Modeling of Osteosarcoma with Induced Pluripotent Stem Cells. Stem Cell Res. Dec;49:102006.
- Li H, Tu J, Zhao Z, Chen L, Qu Y, Li H, Yao H, Wang X, Lee DF, Shen J, Wen L, Huang G, Xie X. (2020). Molecular signatures of BRCAness analysis identifies PARP inhibitor Niraparib as a novel targeted therapeutic strategy for soft tissue Sarcomas. Theranostics. Jul 25;10(21):9477-9494.
- Li A, Mallik S, Luo H, Jia P, Lee DF, Zhao Z. (2020). H19, a Long Non-coding RNA, Mediates Transcription Factors and Target Genes through Interference of MicroRNAs in Pan-Cancer. Mol Ther Nucleic Acids. Sep 4; 21:180-191.
- Huo Z, Tu J, Lee DF, Zhao R. Engineering Mutation Clones in Mammalian cells with CRISPR/Cas9. Methods Mol Biol. 2108:355-369, 2020.
- Wen MH, Xie X, Tu J, Lee DF, Chen TY. (2019). Generation of a genetically modified human embryonic stem cells expressing fluorescence tagged ATOX1. Stem Cell Res. Dec;41:101631.
- Su J, Zhu D, Huo Z, Gingold JA, Ang YS, Tu J, Zhou R, Lin Y, Luo H, Yang H, Zhao R, Schaniel C, Moore KA, Lemischka IR, Lee DF. (2019). Genomic Integrity Safeguards Self-Renewal in Embryonic Stem Cells. Cell Rep. Aug 6;28(6):1400-1409.e4.
- Wang D, Luo H, Huo Z, Chen M, Han Z, Hung M, Su B, Li Y, Wang X, Guo X, Xiao H, Lee D, Zhao R, Yang H. (2019). Irradiation-induced dynamic changes of gene signatures reveal gain of metastatic ability in nasopharyngeal carcinoma. Am J Cancer Res. Mar 1;9(3):479-495.
- Jewell BE, Liu M, Lu L, Zhou R, Tu J, Zhu D, Huo Z, Xu A, Wang D, Mata H, Jin W, Xia W, Rao PH, Zhao R, Hung MC, Wang LL, Lee DF.(2018). Generation of an induced pluripotent stem cell line from an individual with a heterozygous RECQL4 mutation. Stem Cell Res. Dec;33:36-40.
- Kim HS, Yoo S, Zhou R, Xu A, Bernitz JM, Yuan Y, Gomes AM, Daniel MG, Su J, Demicco EG, Zhu J, Moore, KA, Lee DF*, Lemischka IR, Schaniel C*. (2018). Oncogenic role of SFRP2 in p53-mutant osteosarcoma development via autocrine and paracrine mechanism. Proc Natl Acad Sci U S A. Nov 20;115(47):E11128-E11137. (*corresponding author)
- Zhu D, Kong CSL, Gingold JA, Zhao R, Lee DF. (2018). Induced pluripotent stem cells and induced pluripotent cancer cells in cancer disease modeling. Adv Exp Med Biol. 1119:169-183.
- Liu M, Tu J, Gingold JA, Kong CSL,Lee DF. (2018). Cancer in a dish: Progress using stem cells a platform for cancer research. Am J Cancer Res. Jun 1;8(6):944-954.
- Zhou R, Xu A, Tu J, Liu M, Gingold JA, Zhao R, Lee DF. (2018). Modeling osteosarcoma using Li-Fraumeni syndrome patient-derived induced pluripotent stem cells. J Vis Exp.Jun 13;(136).
- Xu A, Zhou R, Tu J, Huo Z, Zhu D, Wang D, Gingold JA, Mata H, Rao PH, Liu M, Mohamed AMT, Kong CSL, Jewell BE, Xia W, Zhao R, Hung MC, Lee DF. (2018). Establishment of a human embryonic stem cell line with homozygous TP53 R248W mutant by TALEN mediated gene editing. Stem Cell Res. Apr 27;29:215-219.
- Gingold JA, Zhu D, Lee DF, Kaseb A, Chen J. (2018). Genomic Profiling and Metabolic Homeostasis in Primary Liver Cancer. Trends Mol Med. Apr;24(4):395-411.
- Zhou R, Xu A, Wang D, Zhu D, Mata H, Huo Z, Tu J, Liu M, Mohamed AMT, Jewell BE, Gingold J, Xia W, Rao PH, Hung MC, Zhao R, Lee DF. (2018). A homozygous p53 R282W mutant human embryonic stem cell line generated using TALEN-mediated precise gene editing. Stem Cell Res. Jan 26;27:131-135.