The following are projects that Dr. Yang and his lab members are involved in:
MAPK4 Biology in Human Cancers
MAPK4 is an atypical MAPK that were not well studied. MAPK4 biology in human diseases, including cancers, remain largely unknown. We discovered that MAPK4 activates the Akt/mTOR signaling pathway along with several other key pathways to promote cancer initiation, progression, and the development of therapy-resistance. We are now pioneering the research on MAPK4 biology in human cancers and are carrying out in-depth studies to reveal the molecular mechanisms underlying MAPK4 regulation of human cancers.
Targeting GATA2 Degradation as Novel Therapeutic Approach for Therapy-Resistant Prostate Cancer
Androgen deprivation therapy (ADT) is the standard therapy for advanced/metastatic prostate cancer (PCa). However, patients inevitably develop the lethal castration-resistant PCa (CRPC) including those resistant to the most advanced therapies using enzalutamide, apalutamide, and abiraterone. Taxane chemotherapy is the first-line treatment for CRPC; however, resistance rapidly occurs. Most CRPCs and taxane-resistant CRPCs remain AR-dependent while the AR- CRPCs are increasingly being observed. GATA2 is a transcription factor and pioneer factor crucial for inducing AR expression and activation in PCa. It can also promote PCa resistance to taxane chemotherapy independent of AR. Therefore, GATA2 is emerging as a therapeutic target for the lethal CRPC/taxane-resistant CRPC. Although it is challenging to directly inhibit GATA2 transcriptional activity, GATA2 protein is unstable, which makes further enhancing GATA2 protein degradation a promising therapeutic avenue. However, how GATA2 protein stability is regulated in PCa remains largely unknown. Over the last five years, we have characterized the detailed molecular mechanism regulating GATA2 stability in PCa. We are now investigating targeting GATA2 degradation as a novel therapeutic approach for prostate cancer, especially the lethal CRPC and taxane-resistant CRPC.
A Versatile Model for Efficient and Tumor-Specific Gene Manipulation in Vivo
We have developed a versatile gene delivery system for efficient and tumor specific gene manipulation in vivo. This includes the RCI-Oncogene/TuKO (tumor specific knockout of gene of interest) system that we have used in revealing a crucial role of FGFR1 in promoting breast cancer progression and metastasis. A detailed protocol can be found here.
Ai-MYC Tumor Model for Cre-Induced Tissue-Specific Expression of c-Myc in Vivo
c-Myc is one of the most significantly amplified oncogenes in human cancers, including prostate cancer. The Hi-MYC prostate cancer model, along with other similar Myc-based models, documented the key roles of c-Myc oncogenic pathway in prostate tumorigenesis. However, since the Hi-MYC model used an enhanced androgen-dependent probasin promoter to drive c-Myc expression, the tumors lose c-Myc expression upon castration. Therefore, the castration-induced tumor regression 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 significantly limited 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 Ai-MYC 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 cancer, as well as other human diseases.
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.