Lee and Zhao Labs: Overview
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The Lee and Zhao Lab is featured on the McGovern Medical School Instagram at UTHouston Health.
Lab Takeovers
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The editors at Nature Communications have put together an Editors’ Highlights webpage of recent research called “Cancer”. Drs An Xu and Mo Liu's article entitled “Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation” is chosen as a featured article by Nature Communications Editor Dr. Stephanie Koo.
Dissect Cancer Pathogenesis by iPSC Approaches
After leukemia and brain tumor, osteosarcoma is one of the 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 Yamanaka 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 understanding cancer pathological mechanisms by applying patient-specific iPSCs and/or engineered ESCs (Gingold J et al. Trends Cancer 2016). 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 2015; Zhou et al. Trends Pharmacol Sci 2017; Kim et al. PNAS USA 2018; Xu et al. Front Genet 2021; Choe et al. Cancer Discov 2023; Xu et al. Nat Commun 2023). 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.
Stem Cell Lab
Current Research projects
(1) Systems-level analysis and functional characterization of mutant p53 in LFS-associated cancers. We utilize patient-derived LFS-induced iPSCs together with genome engineering technologies, including TALEN and CRISPR/Cas9, to generate defined p53 mutations in PSCs, including iPSCs and ESCs. These engineered p53-mutant PSC models recapitulate key features of LFS and are differentiated into tissue-specific cells of origin for multiple cancer types, including osteoblasts for osteosarcoma, myogenic progenitors for rhabdomyosarcoma, astrocytes for astrocytoma, and hepatocytes for liver cancer. We then perform comprehensive molecular profiling using transcriptomic, miRNA, interactome, and ChIP-seq analyses to define genome-wide alterations induced by mutant p53. Integration of these multi-omic datasets provides insights into the tumor suppressive functions of p53 across diverse tissues and reveals shared oncogenic pathways driven by distinct p53 mutations.
(2) Modeling hereditary cancer predisposition syndromes using patient-specific iPSC platforms. To identify common mechanisms underlying inherited cancer susceptibility, we develop patient-specific iPSC models of hereditary cancer syndromes driven by diverse genetic alterations. These models enable us to investigate the central molecular events that initiate tumorigenesis and promote malignant transformation. Our current efforts focus on hereditary cancer predisposition disorders including hereditary retinoblastoma (RB), Rothmund–Thomson syndrome (RTS), and Diamond–Blackfan anemia, among others.
(3) Development of advanced PSC-based differentiation platforms for cancer research and regenerative medicine. To facilitate future applications of iPSCs and human ESCs in cancer biology, tissue regeneration, and translational medicine, we integrate lineage-specific fluorescent reporter systems with artificial intelligence (AI)-assisted approaches to optimize and refine both two-dimensional (2D) and three-dimensional (3D) differentiation methodologies. These platforms enable improved efficiency, reproducibility, and scalability in generating lineage-specific cell types and organoid models.
(4) Investigating the fundamental mechanisms of bone biology and osteoblast differentiation. To better understand the molecular basis of bone biology, we employ systems biology approaches, next-generation sequencing technologies, and genetically engineered mouse models to dissect osteoblast-specific gene regulatory networks and determine how extracellular signaling pathways influence osteoblast differentiation, maturation, and function.
Additional Lab information
Dr. Dung-Fang Lee
McGovern Medical School, UTHealth Houston
https://med.uth.edu/ibp/2022/11/01/dung-fang-lee-phd/
The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences
https://gsbs.uth.edu/directory/profile?id=ea67dc12-917b-44dc-a289-aa9e79235bce
Research.com
https://research.com/u/dung-fang-lee
Dr. Ruiying Zhao
McGovern Medical School, UTHealth Houston
https://med.uth.edu/ibp/2022/11/01/ruiying-zhao-md-phd/
Modeling Cancer with Stem Cells
https://www.youtube.com/watch?v=88cl5Fpg6OI
JOVE Videos
Modeling Osteosarcoma Using Li-Fraumeni Syndrome Patient-derived Induced Pluripotent Stem Cells https://www.jove.com/t/57664/modeling-osteosarcoma-using-li-fraumeni-syndrome-patient-derived
The Lee and Zhao Labs locate in the McGovern Medical School at the University of Texas Health Science Center at Houston. Our research is made possible by funding from The University of Texas Health Science Center at Houston, National Cancer Institute, Cancer Prevention and Research Institute of Texas, Department of Defense, Rolanette and Berdon Lawrence Bone Disease Program of Texas, and The Pablove Foundation.
