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Targeting tumor-macrophage interaction via the Notch2-Jag1 axis reverses tumor resistance to paclitaxel

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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE158569 | GEO | 2021/06/29

REPOSITORIES: GEO

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Targeting tumor-macrophage interaction via the Notch2-Jag1 axis reverses tumor resistance to paclitaxel

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