Does the Loss of Stromal Caveolin-1 Remodel the Tumor Microenvironment by Activating Src-Mediated PEAK1 and PI3K Pathways?
Abstract
My goal over the next few years is to apply state-of-the art functional and quantitative proteomic technologies to understand mechanisms of prostate cancer progression to end-stage disease. My long-term goal is to successfully compete for an independent prostate cancer investigator. The training program will provide me a great opportunity to broaden my knowledge in prostate cancer, enable me to master some state-of-the-art techniques, improve my professional skills such as writing grants, presenting research findings, writing research articles for publication, and help me to acquire leadership and organizational experience. The research plan will allow me to apply my expertise in proteomics to study the mechanisms underlying prostate cancer development and progression, which may open up unexpected avenues for therapeutic intervention in prostate cancer. Overall, the training award will facilitate my development into an independent and productive investigator in prostate cancer research. Prostate cancer is the second leading cause of cancer death in American men and kills about 28,000 American men every year. Although progress has been made in understanding the molecular features of different forms of the disease, prostate cancer is typically incurable when it is diagnosed too late. So it is very important to diagnose the prostate cancer early, before progression to advanced disease. Here, we aim to reveal the molecular mechanism underlying how the microenvironments regulate the tumor progression and try to discover novel biomarkers and therapeutic targets. It has gradually become clear that the tumor stromal environment, also called the tumor microenvironment (TME), plays a crucial role in the initiation, progression, and metastasis of cancer; hence, targeting the TME has emerged as a novel therapy for cancer treatment. The TME consists of many different types of cells (e.g., fibroblasts/myofibroblasts, vascular cells, immune cells, etc.) along with the extracellular matrix (ECM) and extracellular molecules. Though many classic extracellular signaling molecules (e.g., hormones, peptide growth factors, and cytokines) are water-soluble, increasing evidence has shown that a variety of extracellular molecules are confined in extracellular vesicles (EVs) such as exosomes and microvesicles and that EV-mediated intercellular communication plays an important role in cancer progression. Thus, we hypothesize that the loss of Cav1 in prostate stroma may remodel the TME and thus facilitate PCa progression, at least in part, by degrading the ECM (a critical step for cell invasion and tissue transmigration) and by regulating the secretion of certain extracellular molecules, either in water-soluble or EV-confined form. The overall objective is to test the hypothesis that the loss of Cav1 in prostate stroma promotes PCa progression and metastasis, at least partly, by activating the Src-mediated PEAK1 and PI3K pathways and by regulating the release of certain extracellular proteins. We will identify these differentially secreted proteins and then determine the functions of select proteins whose roles in the prostate cancer microenvironment are undefined. These proteins may serve as biomarkers and for microenvironment-targeted therapies. The patient with malignant prostate tumors will be diagnosed earlier, which is very important for the relapse-free survival. In addition, therapeutic targets in microenvironment are easier to effect than those in cells, since they are exposed to the body fluid. If successful, the proposed study will reveal novel molecular mechanisms of how the loss of stromal Cav1 remodels the TME and thus promoting PCa progression. It will lead to the discovery of novel TME biomarkers that may be used to detect malignant PCa at an early stage. It will also provide novel therapeutic targets for anti-TME therapy. Moreover, because the loss of stromal Cav1 is associated with poor prognosis in many other
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510473
Entities
People
- Mingrui An
Organizations
- Cedars-Sinai Medical Center
- United States Army