Renal Cancer Metastasis: Molecular Mechanisms to Therapy

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Renal cell carcinoma (RCC) is among the 10 most common malignancies in both men and women. It is also a malignancy that is prevalent in the Veteran population. A recent analysis of VA Central Cancer Registry (VACCR) data demonstrates that cancer of the kidney is the fourth most common cancer in the veteran population. The vast majority of studies on RCC biology have focused on primary tumors including recent large-scale sequencing data sets. Patients with disease confined to the kidney have excellent outcomes. In contrast, the development of metastasis is the seminal event that occurs in patients who succumb to this disease. While there are several approved therapies for advanced renal cancer, the reality is that progress in the treatment of metastasis with systemic therapies has been incremental. This fact mandates the need for new therapeutic approaches. The objective of this proposal is to identify the key alterations specifically in metastasis and to use this information to improve the outcomes of those affected with this disease. Transcriptomic analysis of normal kidney, primary RCC, and metastatic RCC samples demonstrates that loss of expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1) is a metastasis-associated alteration. This transcription factor has an established role in mitochondrial and fatty acid metabolism as well as other metabolic pathways. Prior studies in cancer have demonstrated conflicting roles for this factor in cancer. Preliminary studies demonstrate that restoration of PGC1 expression in kidney cancer cells suppresses invasive phenotypes in vitro and metastasis in vivo. In addition to loss of this factor, metastatic tissues are notable for increased expression of several collagen genes. Preliminary data indicates that collagens promote invasive behavior in RCC cells. Based on these preliminary data, the central hypothesis of this proposal is that PGC1 suppresses metastasis by coordinating its epigenetic and metabolic programs to inhibit pro-invasive signaling. The central hypothesis, based on strong preliminary data, will be tested through pursuit of the following specific aims: 1) determine the epigenetic basis by which PGC1 suppresses metastasis, 2) determine the role of metabolism in supporting collagen biosynthesis in renal cancer cells, and 3) determine the mechanisms by which collagen promotes invasive behavior. The proposal has translational significance as the information gathered from each aim could pave the way for new treatment strategies for patients with advanced RCC. Ultimately, the knowledge gathered has the potential to improve the efficacy of treatment for Veterans with advanced RCC, an unmet need challenging the contemporary management of this disease.