Summary of current lab research activity.
The overall goal of our laboratory is to understand the molecular and cellular basis of cancer promotion and metastatic progression. Currently, the Cinar Laboratory studies the molecular interactions between Hippo-YAP pathway and androgen hormone receptor and PI3-Kinase-mTOR signaling. Our approach utilizes tissue culture, animal models, genetics, bioinformatics and imaging modalities.
Current research in the lab focuses on prostate tumor biology. Prostate cancer, one of the most common causes of cancer deaths in western societies,evolves as an androgen-dependent disease. This disease frequently reappears as a castration-resistant, lethal phenotype, which poses significant clinical challenges. Molecular mechanisms contributing to the lethal progression of castration-resistant and metastatic disease are poorly understood. Mounting evidence suggests that the activation of androgen receptor (AR) alone and/or together with PI3K-Akt and mTOR pathway plays a central role in prostate tumor promotion and metastasis. The Hippo-YAP pathway has emerged as an important regulator of cell growth, organ size control, stem cell self-renewal, and tumorigenesis, as suggested by clinical and preclinical studies. Studies of our own and others have suggested that Hippo-YAP pathway is a promising drug target in the fight against cancer.
These cancer drugs show anti-tumor activity in preclinical and clinical studies.
Role of Hippo Signaling in Prostate Cancer Progression
The Cinar Laboratory has been studying the role of Hippo (MST1/2 protein kinase) signaling in prostate tumor biology. Published studies from our laboratory have indicated that the deregulation of Hippo could play a prominent role in prostate tumor progression and metastasis in humans. We want to explore the possibility as to whether there is a direct role for Hippo in prostate tumor promotion and metastatic progression. To address these key questions, our lab has developed a conditional Hippo-knockout (MST1/2-KO) mouse prostate model using Cre/LoxP-mediated excision approach. Our preliminary investigations suggest that mouse prostate lacking Hippo developed epithelial hyperplasia and the prostate intraepithelial neoplasia, a precursor of prostate cancer. We will utilize this genetically engineered mouse model to explore the molecular and cellular basis of how MST/Hippo contributes to prostate epithelial cell transformation and tumor progression.
Functional Association Between YAP and AR Signaling in Prostate Cancer
YAP (yes associated protein, related to Yki in drosophila) is a transcriptional co-activator, regulates gene expression and contributes to oncogenic cell transformation. YAP was identified as a prominent MST/Hippo nuclear effector. MST/Hippo phosphorylates and inhibits YAP activity. The loss-of-function of Hippo leads to YAP activation via increasing YAP protein and nuclear abundance. The molecular interaction between steroid hormone receptors and YAP is yet to be defined. Our lab has published and showed that MST/Hippo might function as a potent physiologic negative regulator of AR and androgenic signaling in prostate cancer cells. These findings suggest the possibility that YAP may play a key role in the inhibition of androgenic signaling by MST/Hippo. Currently, the lab is exploring the biochemical and functional link between YAP and AR and investigating the possibility that YAP plays a significant role in metastatic prostate tumor progression and treatment resistant targeting of AR and/or PI3K-mTOR pathway signaling.
Molecular Mechanisms of Hippo Deregulation in Prostate Cancer Cells
Regulation of MST/Hippo signaling is a complex process. Reduced expression, lack of cleavage, altered subcellular localization, and altered phosphorylation at key residues have been suggested to deregulate MST/Hippo cellular functions. For example, CD44 and G-protein coupled receptor (GPCR) have been implicated in MST/Hippo deregulation. A published study from this laboratory has shown that signals initiated or mediated by PI3K and/or mTOR pathway partially diminished MST/Hippo functions in prostate cancer cells. These findings suggest possibility that multiple signaling mechanisms target and alter MST/Hippo functions. Our laboratory is currently exploring these possibilities by using genetically modified MST/Hippo prostate cancer cell models and attempting to identify gene signatures that reflect changes in MST/Hippo signaling by using genomic and bioinformatics approaches.
A side from these studies, the Cinar Laboratory begins to explore the functional potentials of Hippo-YAP pathway in lung cancer progression and treatment resistance, especially resistance to EGFR-tyrosine kinase inhibitor Erlotinib. We are collaborating with Dr. Ronald Natale, a Director of Lung Cancer Institute at Cedars-Sinai, to explore these possibilities.
The New York Academy of Medicine
Donna and Jessie Garber Foundation
UCLA Clinical and Translational Science Institute