肿瘤微环境中的ATP通过P2RY2受体促进胰腺导管腺癌的生长和有氧糖酵解

Pancreatic cancer is a kind of digestive tract tumor difficult to diagnose and treat, 90% of which is Pancreatic ductal adenocarcinoma (PDAC). ATP, as a carrier of energy and genetic information, is also an extracellular signaling molecule, plays an important role in tumor microenvironment. However, the role and related molecular mechanism of ATP and its receptor in pancreatic cancer remain unclear. In this study we found that ATP could promote the proliferation of PDAC cells. By analyzing TCGA and GEO datasets, and in vitro and in vivo experiment, we found that ATP worked mainly through its receptor P2RY2. Further studies showed that activated P2RY2 receptor could interact with Yes1, which belongs to Src family, and recruited p85 to activate the signaling molecules in PI3K-AKT-mTOR pathway, thereby enhancing glycolysis and promoting the proliferation of PDAC cells. Further, we will use pancreatic cancer model KPC mice to confirm above results, and analyze the clinical significance of ATP and P2RY2 receptor, and the possibility of regarding P2RY2 as a therapeutic target. This study will provide new ideas and solutions to improve the diagnosis and treatment of pancreatic cancer from the way of tumor microenvironment.

胰腺癌是一种诊断和治疗困难的消化道肿瘤，其中90%为胰腺导管腺癌。ATP作为能量和遗传信息的载体，同时也是一个细胞外的信号分子，在肿瘤微环境中发挥着重要的作用，而ATP及其受体在胰腺癌中的作用及相关分子机制到目前为止仍不清楚。申请人通过前期的研究发现肿瘤微环境中的ATP可促进胰腺导管腺癌细胞的增殖。通过分析TCGA和GEO等数据库以及体内外实验，发现ATP主要是通过其受体P2RY2发挥作用。进一步的研究发现P2RY2受体活化后，可通过与Src家族的Yes1蛋白相互作用，招募p85以激活PI3K-AKT-mTOR通路上的信号分子，从而增强肿瘤细胞的糖酵解并促进胰腺导管腺癌细胞的增殖。之后申请人拟在胰腺癌模型KPC小鼠中进行验证，并结合临床样本分析ATP及其受体P2RY2的临床意义及作为治疗靶点的可能性。本课题将从肿瘤微环境方面着手为改善胰腺癌的诊疗提供新的思路和方案。

胰腺癌是一种诊断和治疗困难的消化道肿瘤，其中90%为胰腺导管腺癌。ATP作为能量和遗传信息的载体，在肿瘤微环境中发挥着重要的作用，而ATP及其受体在胰腺癌中的作用及相关分子机制到目前为止仍不清楚。申请人通过研究发现肿瘤微环境中的ATP可促进胰腺导管腺癌细胞的增殖。通过分析TCGA和GEO等数据库以及体内外实验，发现ATP主要是通过其受体P2RY2发挥作用。进一步的研究发现P2RY2受体活化后，可通过与Src家族的Yes1蛋白相互作用，招募p85以激活PI3K-AKT-mTOR通路上的信号分子，从而增强肿瘤细胞的糖酵解并促进胰腺导管腺癌细胞的增殖。本课题从肿瘤微环境方面为改善胰腺癌的诊疗提供了新的思路和方案。