Education

Postdoctoral Fellow
Icahn School of Medicine at Mount Sinai, 2016
Ph.D.
Graduate School of Biomedical Sciences, M.D. Anderson Cancer Center, The University of Texas Health Science Center, Houston, 2008

Areas of Interests

Research Interests

iPSC Disease Modelling, Cancer Pathological Mechanisms

Research Information

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.

Publications

Publication Information

REFERENCES

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    * Recommended in F1000 Prime (http://f1000.com/prime/725429874)
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  • 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.
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  • 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.
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  • 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.