![]() ![]() 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. 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. 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. This finding opens an exciting new area to search for new vulnerabilities in breast cancer cells. Surprisingly, CBFB exerts its suppressive function by regulating the translation of hundreds of mRNAs (Malik et al, Nature Communications, 2019). Recently, we found that CBFB and its binding partner RUNX1 have a tumor suppressive function in some subtypes of 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. Interestingly, recent genome-wide sequencing studies revealed that CBFB and RUNX1 were highly mutated in human breast tumors. Potent CBFB inhibitors have been developed by other groups. Therefore, one attractive strategy could be targetting CBFB. The activity of RUNX2 relies on its transcription co-factor, CBFB. This observation suggests that the RUNX2 signaling pathway may be a actionable vulnerability in osteosarcoma cells. Furthermore, we found that human osteosarcoma cells but not MSCs are dependent on RUNX2 to survive (Shin et al., PLOS Genetics, 2016). 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). ![]() 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. MSCs are proposed to be one of the cells of origin of osteosarcoma. One component of this project is to Investigate osteosarcomagenesis using mesenchymal stromal/stem cells (MSCs) as a model. Project 2: Vulnerabilities in osteosarcoma and breast cancer. 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. 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). We and others have found that p53 plays important roles in the regulation of ESC differentiation after DNA damage. We aim to address this question by studying how p53 regulates the DNA damage responses of ESCs. However, it is under appreciated how ESCs maintain their genome stability responding to DNA damage insults. Therefore, maintaining genomic stability and homeostasis is essential for ESCs to execute lineage choice. ESCs can develop into many different cell types and have huge potential in cell therapy. Through these basic studies, our goal is to generate novel insights into tumorigenesis and design new ways of killing caner cells. We are collaborating with intramural and extramural colleagues to study breast cancer. My laboratory has extensive experience in embryonic stem cells (ESCs), mesenchymal stromal/stem cells (MSCs), and osteosarcoma (OS). Recently, we have extended our studies into transcription factors that functionally interacts with p53. Historically, we have been studying the tumor suppressor p53, also called the guardian of the genome. We are interested in the biological functions of transcription factors that may play critical roles in both stem cell and cancer biology. My research interest is focused on gene expression regulation in stem cell and cancer. ![]()
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