上海交通大学于颖彦教授揭示极光激酶抑制剂诱导的胃癌类器官衰老可削弱巨噬细胞的天然免疫反应

研发靶向弥漫型胃癌的药物具有重要意义。 肿瘤 细胞 分泌大量的炎症趋化因子 MCP-1/CCL2 ，诱导单核巨噬细胞聚集并发生 M2 极化，导致原本来杀伤肿瘤的机体天然免疫巨噬细胞 杀伤力减弱 。 Diffuse-type gastric cancer (DGC) isasubtype ofgastric cancerwithaggressiveness andpoor prognosis. It is of great significance to find sensitive drugsforDGC.Inthecurrent study,a total of 20 patient-derived organoids(PDOs) were analyzed for screening the therapeutic efficacy of small molecule kinasesinhibitors ongastric cancers, especially the therapeutic difference betweenintestinal-typegastric cancer(IGCs) and DGCs. The IGCsaresensitive to multiple kinasesinhibitors,whileDGCsareresistanttomost of these kinasesinhibitors. It was found that DGCs showed drug-induced senescent phenotype aftertreatment by aurora kinasesinhibitors(AURKi) Barasertib-HQPA and Danusertib. The cell diameter of cancer cells are increased withstronger stainingof senescence-associated β-galactosidase (SA-β-GAL),andcharacteristic appearance of multinucleated giant cells.The senescent cancer cellssecrete large amounts of chemokine MCP-1/CCL2, whichrecruitand inducemacrophage to M2-type polarizationin PDOs of DGC (DPDOs)-macrophage co-culturesystem.The up-regulation of localMCP-1/CCL2can interact withMCP-1/CCL2 receptor (CCR2)expressed onmacrophagesand suppress theirinnate immunitytocancer cells.Overall, the special response of DGC to AURKisuggests that clinicians should select asequential therapy withsenescent cell clearanceafter AURKitreatment for DGC.。