Dissecting the Periostin-Directed Metastatic Cross Talk in Clear Cell Renal Cell Carcinoma
Abstract
Background: Kidney cancer is the seventh leading cancer in the United States. Each year, more than 60,000 Americans are diagnosed with primary kidney cancer. Clear cell renal cell carcinoma (ccRCC) is the most common subtype, accounting for 80% of all cancers of the kidney. The clinical course of ccRCC is remarkable for its high frequency of dissemination (metastasis) to the lung. Patients with lung metastasis have very poor outcomes with 5-year survivals of around 10%. A unique genetic feature of ccRCC is that greater than 70% of cases involve mutation or deletion of the VHL gene, but the precise role of the VHL gene in the development of ccRCC and its metastasis is unclear. Recently, we created a new implantable ccRCC mouse model by deleting the VHL gene in ccRCC cell lines. This model revealed a completely new process of tumor dissemination. The parental VHL-expressing tumor cells (called VHL-WT cells) can form tumors in the kidney but do not metastasize. The VHL gene-deleted tumor cells (called VHL-KO cells) alone cannot form primary tumors or metastasize. Interestingly, when VHL-KO cells are implanted together with VHL-WT cells into the mouse kidney, they form robust primary tumors and fulminant metastasis in the lungs. Our model suggests that a tumor can contain different subpopulations of tumor cells that cross-communicate and cooperate with each other to advance the cancer. Specifically, the VHL-KO cells are the cell population that drives metastasis. Furthermore, we discovered that periostin (POSTN) is a secreted factor produced by VHL-KO cells that promotes ccRCC metastasis. We postulate that the POSTN secreted by the VHL-KO cells promotes the growth and motility of the VHL- WT cells. Additionally, POSTN causes damage to blood vessels to open the path for tumor cell escape from primary tumor to the lung. The research strategies of this KCRP project are to further investigate the cross- communication between the two tumor cell populations and clarify the functional role of POSTN in the metastatic process. In this project, we will examine the functional activity of POSTN in engineered ccRCC cell lines, a new patient tumor-derive xenograft model as well as patient tumor tissue sections. Furthermore, we will test the therapeutic activity of a potent POSTN-blocking antibody as a treatment to halt metastasis in our metastasis models. This project specifically addresses the New Disease Model Systems, Biomarker Development and Therapeutic Development of the FY19 KCRP Area(s) of Emphasis. Innovation: This project is unique and innovative in many aspects. First, the concept that distinct tumor cell populations are working in concert to cause metastasis is a new and important idea. This concept stresses the need to find better treatments by targeting the right driver population. Second, the metastatic ccRCC mouse models we developed are novel as there is no clinically relevant animal model currently available to study or test treatment for metastasis. Third, we identified POSTN as a soluble factor secreted by the metastatic driver population (VHL-KO cells) that could play a key role in facilitating metastasis. Fourth, we have generated eight new patient-derived ccRCC xenografts in CAM. In particular, we will concentrate on CAM PDX derived from a very aggressive case (PD#22), which will provide a clinically relevant model to investigate our hypothesis. Finally, we also obtained a highly active POSTN-blocking antibody from our collaborators in Belgium. This antibody could serve as a new therapeutic agent to inhibit metastasis. With the great number of valuable resources at hand, we are well-situated to advance the understanding of metastatic renal cancer and develop a new biomarker and therapy to treat this deadly stage of this cancer. The long-term benefit of this project is to gain a better understanding of how metastasis occurs and devise a novel, effective treatment targeting this important cr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010918
Entities
People
- Lily Wu
Organizations
- United States Army
- University of California, Los Angeles