|Institution||Baylor College of Medicine|
|Department||Department of Molecular & Cellular Biology|
|Address||Molecular & Cellular Biology Department|
One Baylor Plaza
Houston TX 77030
2008||Exploration-Hypothesis Development Award |
2012||New Investigator Award |
2010||Concept Award |
2016||Individual Investigator Research Award |
2016||Idea Development Award |
2016||Idea Development Award|
The research in my laboratory focuses on the following four major areas.
(1) MAPK4 in regulating key signaling pathways in human cancers. MAPK4 is an atypical MAPK that were not well studied. Unlike other “typical” MAPK such as p38a/b/g, Erk1/2, JNK1/2/3, etc., MAPK4 lacks the highly conserved TXY activation motif that can be phosphorylated by MAPKK, the dual Ser/Thr and Tyr kinase. Instead, MAPK4 carries the SEG motif that lacks a key Tyr (Y) residue for phosphorylation by MAPKK. Hence, there is no identified MAPKK for MAPK4. PAKs were shown to phosphorylate MAPK4/Erk4 and MAPK6/Erk3 (another atypical MAPK). However, the biological significance of PAKs in MAPK4 activation remains to be determined. Currently, the roles of MAPK4 in human cancers are unknown. We discovered that MAPK4 regulates several key signaling pathways that are essential for cancer progression as well as the development of therapy-resistance. We are now carrying out in-depth studies to reveal the molecular mechanisms underlying MAPK4 regulation of human cancers, focusing on prostate cancer.
(2) Tumor microenvironment regulation of prostate cancer. Tumor microenvironment, including stromal cells, has been documented to play key roles in regulating human cancers. Our study revealed that prostate stromal cells profoundly regulate prostate cancer biology, including inducing androgen-dependent and androgen-independent AR activation. We are now investigating the detailed molecular mechanisms underlying this tumor stroma-induced AR activation in prostate cancer cells in the absence of significant amount of androgen. This may provide a direct mechanism for relapse of the lethal castration-resistant prostate cancer after androgen-deprivation therapy.
(3) Development of a novel transgenic model for prostate cancer. c-Myc is the most significantly amplified oncogene in human prostate cancer. Dr. Sawyer’s group has developed the Hi-MYC model using an enhanced probasin promoter to drive c-Myc expression in prostate epithelia. These mice developed invasive prostate carcinomas that shared molecular features with human prostate cancers. This study, along with others, provided crucial data supporting key roles of c-Myc oncogenic pathway in prostate tumorigenesis. However, since probasin promoter activity is crucially dependent on androgen, the prostate tumors lose c-Myc oncogene expression upon castration in such MYC models. Therefore, the tumor regression in these androgen-depleted MYC mice represents the mixed effects of both artificial direct effects from loss of oncogene expression and potential real effects from tumor cellular responses to castration. These greatly limit the abilities to use such models to concisely study androgen signaling, castration-responses, and castration-resistance of prostate cancer. Accordingly, we have developed a novel transgenic model that allows maintained expression of c-Myc oncogene along with luciferase (for real-time in vivo bioluminescence imaging) in prostate after castration. We are performing detailed characterization of this model and using it to study therapy-resistance such as castration-resistance and chemoresistance of prostate cancers.
(4) FGFR1 signaling in prostate cancer and breast cancer. We are also investigating the biological functions of FGFR1 in prostate cancer and breast cancer, focusing on its role in promoting tumor progression and metastasis.
Prostate Cancer, Mouse model, Therapy resistance, Tumor microenvironment
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