CNPY2调控转移前微环境促进黑色素瘤肺转移的分子机制研究

肿瘤转移前微环境在黑色素瘤转移过程中起着关键作用，但机制尚不明确。我们前期筛选了与黑色素瘤转移相关的基因，发现CNPY2表达与黑色素瘤转移呈正相关，但其并未直接影响黑色素瘤细胞的迁移与侵袭能力，而是通过调控骨髓源细胞招募及血管渗漏促进黑色素瘤肺转移，提示CNPY2参与转移前微环境的形成，这为探索黑色素瘤的转移机制开辟了新的视角。在此基础上，本课题拟建立敲除和过表达CNPY2的细胞系、荷瘤小鼠肺转移及转移前模型，进一步从细胞和动物模型层次探讨CNPY2在转移前微环境形成中的作用；进而采用飞行时间质谱、蛋白芯片等技术鉴定CNPY2受体、调控基因及下游通路，揭示其受体、调控基因在骨髓源细胞招募及血管渗漏中的作用；旨在阐明CNPY2调控转移前微环境促进黑色素瘤肺转移的分子机制。本项目具有较好的科学创新性，不但为黑色素瘤转移机制研究提供新的思路，也将为肿瘤转移的诊断、防治提供新的策略和药物筛选靶点。

Premetastatic niche in distant organs maintains a pro-tumor microenvironment to facilitate melanoma metastasis. However, the underlying mechanisms remain elusive. Through gene microarray analysis, we identified that CNPY2 is positively correlated with melanoma malignancy. Knockout of CNPY2 in melanoma cells showed marginal effects on melanoma migration and invasion in vitro. However, CNPY2 augmented melanoma pulmonary metastasis in vivo, accompanied with increases in both the recruitment of bone marrow derived cells (BMDCs) and vasculature permeability in lung tissues, indicating that CNPY2 is involved in the formation of premetastatic niche. This clue provides a new perspective to explore the mechanism of melanoma metastasis. In the current study, the roles of CNPY2 in the premetastatic niche will be further explored in both cellular and animal experiments. To elucidate the biological functions and molecular mechanisms of CNPY2 in regulating the formation of the premetastatic niche, we will explore CNPY2 receptor, regulated gene(s), downstream pathway(s) via the methods of matrix-assisted laser desorption/ ionization time of flight mass spectrometry (MALDI-TOF-MS) and protein chip. Collectively, our innovation-driven research will illuminate a new path for the prevention and the mechanisms study of melanoma metastasis.