Hippo Signaling in Prostate Regeneration and Cancer

Career Goals

My primary career goal is to establish an independent laboratory at a biomedical research institution to conduct basic and translational research to study how prostate tumors originate and develop. Such research is essential for the development of methods to distinguish indolent cancers, in which unnecessary treatment may cause more harm than benefit, from aggressive tumors that will progress rapidly and result in lethality. My mentor, Dr. Michael Shen, is an innovative and accomplished prostate cancer researcher with significant experience in training successful independent researchers. My individualized training will take place in the collaborative and stimulating environment of the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center and will include training in research techniques as well as participation in meetings, journal clubs, seminars, and conferences. This training plan will provide the knowledge and additional research experience that will be necessary for me to establish an independent research program and make valuable contributions in helping prostate cancer patients.

Scientific Rationale and Objective

The prostate is thought to contain adult stem cells, which are cells that can grow and divide in a process of regeneration to heal tissues that have been damaged. In a healthy prostate, these stem cells are strictly controlled so that they grow only when needed. Recent studies have shown that adult stem cells can be regulated by a network of proteins called the Hippo signaling pathway in organs such as the liver and intestine. In normal tissues, Hippo signaling prevents excessive growth by helping to silence a protein called YAP (Yes-associated protein). However, whether the same proteins control the activity of stem cells in the prostate is not known.

It is important to understand how growth of prostate stem cells is regulated, as uncontrolled growth of adult stem cells may lead to the formation of tumors. Supporting this view, studies of the liver using mouse models has shown that too little Hippo signaling or too much YAP can cause stem cells to grow and divide too much, resulting in rapid cancer formation. Defects in the Hippo signaling pathway have been detected in human prostate cancer tissues, but it is not known whether this is just a correlation or whether inactivating this pathway can cause prostate cancer.

The studies proposed in this application will use mouse models to address how the proteins in the Hippo signaling pathway affect prostate regeneration and prostate cancer formation. Specifically, I will inactivate Hippo signaling in a population of adult stem cells in the prostate called CARNs (Castration-resistant Nkx3.1 expressing cells), which our lab has recently identified. I will test whether inactivation of Hippo signaling leads to uncontrolled growth of the prostate. Since inactivation of Hippo signaling in liver, lung, and colorectal cancers has been associated with poor prognosis in human patients, I will also determine how Hippo signaling affects prostate cancer initiation and progression.

Impact

A major challenge in the treatment and management of prostate cancer is to accurately distinguish aggressive cancers from slow-growing prostate cancers in patients with low-grade tumors. My proposed research will provide a better understanding of how the Hippo pathway, which is abnormal in many prostate cancers, affects tumor biology. If the results of these studies suggest that defects in the Hippo signaling pathway can lead to rapid prostate tumor formation and progression in the mouse, future studies using human prostate tumor tissue will be conducted to validate proteins in this pathway as biomarkers for reliably distinguishing aggressive from indolent prostate cancer. Furthermore, these studies will be useful for determining whether the Hippo signaling pathway could be targeted for new and more effective therapeutics that will prevent cancer progression.