Dung-Fang Lee博士

Areas of Interest

Research Interests

beplay苹果手机能用吗研究信息

Dissect Cancer Pathogenesis by iPSC Approaches

After leukemia, osteosarcoma is the second leading cause of cancer mortality among children. Genetic alterations (e.g.,p53突变和RB1删除）与骨肉瘤的开发密切相关。Li-Fraumeni综合征（LFS）的患者是一种由种系突变引起的遗传遗传常染色体显性癌症疾病p53tumor 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.

当前的研究项目beplay苹果手机能用吗

• 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.
• LFS相关骨肉瘤开发过程中基因组改变的系统分析。LFS患者特定的IPSC衍生细胞提供了研究早期基因组改变并确定肿瘤形成所需的第二次打击的理想系统。我们将应用基因组测序来了解与LFS相关骨肉瘤的基因组景观的动态改变。确定的第二次命中代表了预防和治疗LFS患者骨肉瘤的重要治疗靶标。
• 通过患者特异性IPSC方法对家族性癌症综合征进行对骨肉瘤的易感性。为了探索多种遗传性骨肉瘤驱动突变的共同特征，我们将建立其他骨肉瘤疾病模型，以探索触发骨肉瘤发育的中心病理机制。
• We are also interested in modeling genetic diseases with predisposition to cancers but not limited to osteosarcoma.

出版物

出版信息

REFERENCES

• 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，Wals J，Walsh MJ。M（6）通过ZFP217的mRNA甲基化和基因转录的协调可调节多能性和重编程。细胞干细胞。，2015年12月3日； 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.细胞代表。，2015年10月20日； 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，Pa​​patsenko 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.干细胞报告, 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.细胞干细胞. 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。用诱导的多能干细胞对家族性癌进行建模。细胞., 2015 Apr 9;161(2):240-54.
  *细胞视频摘要：用干细胞建模癌症（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，WangJ。全基因组RNAi屏幕鉴定了Snail1和Snail2对建立多能的Nanog依赖性的相对功能。Mol Cell。，2014年10月2日； 56（1）：140-52。
• 金HS，伯尼茨J，Lee DF，lemischka ir。基因组编辑工具，用等源性多能干细胞对人类疾病进行建模。干细胞开发., 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.癌细胞., 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.细胞干细胞., 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协议., 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.癌细胞., 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.癌细胞。，2012年1月17日； 21（1）：105-20。
• 刘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，Du Y，Dhar D，Karin M，Carin M，Chen Ch，Chen CH，悬挂MC。IKKα激活Notch通过FOXA2抑制连接肿瘤发生。Mol Cell., 2012 Jan 27;45(2):171-84.
• 丁Q, Chang CJ,谢X,夏W,杨司法院,王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，Curley SA，Ellis LM，Dubois RN，Hung MC。APOBEC3G在结直肠癌的原位小鼠模型中促进肝转移，并预测人类肝转移。J Clin Invest。，2011年11月； 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.癌症。，2011年11月1日； 71（21）：6878-87。
• Li C，Ao J，Fu J，Lee DF，Xu J，Lonard D，O’Malley BW。磷酸泛素连接酶在致癌共激活器SRC-3/AIB1的信号依赖性蛋白水解中的肿瘤抑制剂作用。Oncogene., 2011 Oct 20;30(42):4350-64.
• 张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年7月31日； 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通过胚胎干细胞核心转录网络介导自我更新和重编程。细胞., 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是造血干细胞的生理调节剂。Blood。，2011年5月12日；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。COP9信号体的亚基6通过稳定MDM2促进小鼠的肿瘤发生，并在人类癌症中上调。J Clin Invest。，2011年3月1日； 121（3）：851-65。