Role of a Neuropilin-2/CXCR4 signaling pathway in the formation of prostate cancer bone metastases

• Applicants: Professorin Dr. Anna Dubrovska; Professor Dr. Lorenz C. Hofbauer; Professor Dr. Michael Helmut Muders
• Subject Area: Pathology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 273676790

Bone metastatic disease is the predominant cause of mortality in patients diagnosed with advanced prostate cancer. Others and we have found a high expression of Neuropilin-2 (NRP2) in human bone metastasis from prostatic adenocarcinoma. NRP2, a non-tyrosine kinase receptor for vascular endothelial growth factor-C (VEGF-C), promotes lymphangiogenesis and is essential for neuronal development. Recently, we have demonstrated that NRP2 facilitates therapy resistance by inducing autophagy in cancer. Yet, the function of NRP2 in prostate cancer bone metastasis remains poorly understood. Our preliminary results suggest that NRP2 controls autophagy by interfering with endosomal maturation. Endosomal maturation is also essential for the trafficking of chemokine receptors like CXCR4 that promotes homing of metastatic prostate cancer cells to the bone. Therefore, we hypothesize that NRP2 is involved in prostate cancer bone metastasis formation by interfering with the function of CXCR4. (I) To test this hypothesis, we will elucidate the role of NRP-2 during G-protein dependent short- and beta-arrestin dependent long-term CXCR4 signaling and CXCR4 intracellular trafficking. Here, intracellular colocalization studies with Rab proteins as well as experiments to detect acitvated CXCR4 downstream targets will be executed. (II) Second, we will study the contribution of NRP2 in the CXCR4 dependent homing process of prostate cancer cells to the metastatic niche of the bone in adhesion and invasion assays and a micro-metastasis mouse model. (III) To validate our data in human tissue, we will study the correlation of NRP2 expression with the time-to-occurrence of bone metastasis and cancer-specific survival in tissue microarrays (TMA) and whole slides of 403 prostate cancer patients. (IV) Because CXCR4 is critical for maintenance of a prostate cancer progenitor cell population, we will finally investigate the function of NRP2 in the self-renewal of prostate cancer cells by analyzing the spherogenic potential in vitro and the number of cells that are necessary to initiate tumor growth (so called limiting dilution assay) in vivo. In summary, our project will expand the understanding of NRP2 with respect to a novel function of this molecule: the interference with trafficking and signaling of chemokine receptors. These studies may result in new treatment avenues that allow targeting the metastatic process in acinar adenocarcinoma of the prostate.

• DFG Programme: Research Grants