Targeting tumor-macrophage interaction via the Notch2-Jag1 axis reverses tumor resistance to paclitaxel
crossref(2021)
摘要
Abstract Taxanes are widely used in chemotherapy, but intrinsic and acquired resistance limit the clinical outcomes. Studies showed tumor interaction with suppressive macrophages plays a key role in taxane resistance, yet therapeutic strategies that deplete or repolarize macrophages are challenging. Here we uncovered a novel tumor-macrophage interaction via Notch2-Jag1 justacrine signaling that can be targeted to sensitize paclitaxel response without affecting the broad macrophage functions. Using translatome profiling, we identified Notch2 upregulation during taxol-induced prolonged mitosis. Notch2 was subsequently activated in the post-mitotic G1 phase by Jag1 expressed on neighboring macrophages, which promoted tumor cell survival by upregulating p38 and anti-apoptotic proteins. Notch2 also upregulated cytokines that further recruited Jag1-expressing macrophages. By targeting this Notch2-Jag1 interaction with a pan-Notch inhibitor, RO4929097, taxol resistance was significantly attenuated in multiple mouse tumor models. Our results point to combining Notch inhibitor with taxane as an effective strategy to selectively disrupt tumor-macrophage interaction underlying chemoresistance.
更多查看译文
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要