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We are studying cancer cell signaling with expertise in signal transduction, genetic and epigenetic regulation, and animal models. Our current laboratory research is centered on two families of transcriptional co-activators, MAML and CRTC, which are essential components of Notch receptor signaling and LKB1-CRTC/CREB signaling pathways, respectively. We are investigating the molecular regulation and the roles of deregulated cell signaling in cancer generation and progression, with the goal of gaining molecular insights into cancer pathogenesis and identifying novel cancer diagnostic and therapeutic targets.
Project 1: Identification and functional characterization of a family of MAML transcriptional co-activators.
Notch receptor signaling critically regulates development and tissue homeostasis and is frequently deregulated in human diseases including cancers. In particular, it is a central oncogenic signaling pathway in T-cell acute lymphoblastic leukemia, one aggressive subset of the most common childhood cancer. We previously discovered a family of three MAML (mastermind-like) transcriptional co-activators (MAML1-3) and revealed that an essential, critical downstream step of Notch signaling cascade is the recruitment of MAML co-activators to assemble active Notch transcription complexes. This line of research has guided subsequent generation and elucidation of the crystal structure of Notch transcriptional core complex, providing the basic framework for Notch-activated transcription and a new avenue for Notch signaling modulation. Recently, we identified new biochemical components of the NOTCH/CSL/MAML complexes through proteomic approaches. We are currently performing functional characterizations of prioritized Notch regulator candidates using gene profiling, primary and cultured cells, and mouse models. These studies are expected to reveal fundamental aspects of the Notch pathway and molecular targets for modulating altered Notch signaling in human cancers.
Project 2: Identification, functional characterization, and targeting of CRTC1-MAML2 fusion oncogene.
Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy and also arises in multiple organ sites. Currently, patients with advanced, unresectable MEC have limited therapeutic options and poor treatment outcomes. We previously identified a novel CRTC1-MAML2 fusion gene generated from a recurrent t(11;19)(q14-21;p12-13) in malignant MEC cells. The CRTC1-MAML2 fusion oncogene is associated with more than 50% of human MEC cases and represents a potential major etiologic molecular defect for MEC. CRTC1-MAML2 is essential in maintaining MEC malignant phenotype and thus serves as a promising therapeutic target. Therefore, a better understanding of the biology of this fusion oncogene will provide new targeting opportunities to block MEC. We are currently characterizing the functions and mechanisms of the CRTC1-MAML2 oncogene and exploring approaches to block oncogene functions using various models including human MEC cell lines and xenografts, primary human tumors, and the genetically engineered mouse model of MEC. These studies are expected to provide significant insights into CRTC1-MAML2 fusion-induced tumorigenesis and establish new diagnostic and therapeutic targets for further translation assessment in human MEC.
Project 3: Investigations into deregulated LKB1-CRTC signaling in human cancers.
The tumor suppressor gene LKB1 is inactivated in many sporadic cancers. LKB1 inactivation is associated with poor prognosis and influences the responsiveness of cancer cells to treatments in vitro and in mouse models. However, no accurate diagnostics and effective targeted therapeutics are currently available for LKB1-inactivated tumors. LKB1 has multiple downstream targets, and a novel and important function of LKB1 is its ability to negatively regulate the family of three CRTC co-activators, suggesting a role of CRTC activation in LKB1-deficient tumors. We previously reported an altered LKB1-CRTC signaling pathway in a subset of cancers that promotes cancer cell migration and invasion. We are currently studying the downstream protein-coding and non-coding gene targets of LKB1-CRTC signaling as well as CRTC-interacting proteins. This project is expected to enhance our understanding of the roles and mechanisms of LKB1-CRTC signaling in cancers, and such knowledge will help with diagnosis and treatment of tumors with inactivated LKB1 signaling.
Postdoctoral fellow, Dana-Farber Cancer Institute, Harvard Medical School, Boston
Ph.D., Northeastern University, Boston
B.S., Xiamen University, China
General Motors Cancer Research Scholar Award
American Society of Hematology Scholar Award
GMS6338 Recent Advances in Cancer Metastasis
GMS7194 Biotechnology Seminar
GMS6065 The Fundamentals of Cancer Biology
GMS6036 Advanced Virology
GMS6051 Advanced Signal Transduction
GMS 7980 Doctoral Research
Office: CGRC 362
Lab: CGRC 370G
Phone: (352) 273-8205