My research interest is focused on gene expression regulation in stem cell and cancer. We are interested in the biological functions of transcription factors that may play critical roles in both stem cell and cancer biology. Historically, we have been studying the tumor suppressor p53, also called the guardian of the genome. Recently, we have extended our studies into transcription factors that functionally interacts with p53. My laboratory has extensive experience in embryonic stem cells (ESCs), mesenchymal stromal/stem cells (MSCs), and osteosarcoma (OS). We are collaborating with intramural and extramural colleagues to study breast cancer. Through these basic studies, our goal is to generate novel insights into tumorigenesis and design new ways of killing caner cells.

Project 1: Stress responses of ESCs. ESCs can develop into many different cell types and have huge potential in cell therapy. Therefore, maintaining genomic stability and homeostasis is essential for ESCs to execute lineage choice. However, it is under appreciated how ESCs maintain their genome stability responding to DNA damage insults. We aim to address this question by studying how p53 regulates the DNA damage responses of ESCs. We and others have found that p53 plays important roles in the regulation of ESC differentiation after DNA damage. To achieve this, p53 down-regulates the transcription of many ES cell critical genes (Li et al., Cell Stem Cell, 2015; Zhang et al., Cell Cycle, 2013; Li et al., Molecular Cell, 2012; Lee et al., PNAS, 2010). Current efforts include identifying new players in the p53 signaling network and studying the metabolic stress of ESCs. Since ESCs are derived from blastocysts, representing an early embroynic development stage, our study may shed new light on the roles of p53 in embryonic development and human developmental disorders.

Project 2: Vulnerabilities in osteosarcoma and breast cancer. ​One component of this project is to Investigate osteosarcomagenesis using mesenchymal stromal/stem cells (MSCs) as a model. MSCs are proposed to be one of the cells of origin of osteosarcoma. Although the role of p53 in osteosarcoma suppression is well known, its roles in MSCs and how these roles are related to the osteosarcoma suppressive function of p53 are unclear. We and others have found that p53 represses osteoblastic differentiation of MSCs and p53 loss in osteosarcoma cells correlates well with the up-regulation of RUNX2, a master regulator of osteoblastic differentiation (He et al., Stem Cells, 2015). Furthermore, we found that human osteosarcoma cells but not MSCs are dependent on RUNX2 to survive (Shin et al., PLOS Genetics, 2016). This observation suggests that the RUNX2 signaling pathway may be a actionable vulnerability in osteosarcoma cells. The activity of RUNX2 relies on its transcription co-factor, CBFB. Therefore, one attractive strategy could be targetting CBFB. Potent CBFB inhibitors have been developed by other groups. Interestingly, recent genome-wide sequencing studies revealed that CBFB and RUNX1 were highly mutated in human breast tumors. Therefore, it is important to investigate the role of CBFB in breast cancer, which forms the goal of the second component of this project. Recently, we found that CBFB and its binding partner RUNX1 have a tumor suppressive function in some subtypes of breast tumors. Surprisingly, CBFB exerts its suppressive function by regulating the translation of hundreds of mRNAs (Malik et al, Nature Communications, 2019). This finding opens an exciting new area to search for new vulnerabilities in breast cancer cells. For example, our preliminary studies suggest that CBFB regulates metabolic homeostasis of breast cells, and we have identified a way to effectively kill breast cancer cells bearing CBFB mutations. We extensively collaborate with other Principal Investigators in LCBG on the breast cancer study and expect our studies will contribute to the precision medicine of breast cancer.  

Methods: To achieve our goals, we use various classical and cutting-edge techniques including molecular biology (such as CRISPR), biochemistry (e.g., proteomics), mouse genetics, genomics (e.g., ChIP-seq and RNA-seq), and systems biology.

Training: Our program has strong effort in training with a flexible combination of publication, seminar, and journal club opportunities. Several previous trainees became independent investigators with their own laboratories.

Collaborators (former and current): Intramural: Drs. Stuart Yuspa, Glenn Merlino, Kent Hunter, Lalage Wakefield, Beverly Mock, Ji Luo, Mark Simpson, Rosie Kaplan, Daniel Larson, Pamela Robey, Chengyu Liu. Extramural: Drs. Shelley Berger, Zhaohui Feng, Richard Gorlick