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bioRxiv · 10.1101/2022.12.07.519466

Reactive myelopoiesis and FX-expressing monocyte-derived macrophages triggered by chemotherapy promote cancer lung metastasis

Wu, C.·Zhong, Q.·Shrestha, R.·Wang, J.·Hu, X.·Li, H.·Rouchka, E. C.·Yan, J.·DING, C.
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Abstract

Chemotherapy offers long-term clinical benefits to many cancer patients. However, several pre-clinical studies have demonstrated that certain cytotoxic drugs enhance metastasis via multiple mechanisms. These studies have mainly focused on tumor cell-derived inflammation. The importance of host responses triggered by chemotherapy in regulating cancer metastasis has not been fully explored. Here, we showed that multi-dose Gemcitabine (GEM) treatment promoted breast cancer lung metastasis in a transgenic spontaneous breast cancer animal model. Both CCR2+ macrophages and monocytes were increased in the lungs of GEM-treated mice. Further, the increase of CCR2+ macrophages and monocytes were observed in naive (tumor-free) mice after GEM treatment. These changes were largely caused by chemotherapy-induced reactive myelopoiesis that are biased toward monocyte development. Mechanistically, enhanced production of mitochondrial ROS (mtROS) was observed in GEM-treated BM LSK cells and monocytes. Treatment with the mitochondrial targeted antioxidant abrogated GEM induced hyper differentiation of BM progenitors. In addition, GEM treatment induced up-regulation of host cell-derived CCL2, and CCL2/CCR2 axis played essential role in the pro-metastatic host response induced by chemotherapy. Further, GEM and Paclitaxel (PTX) in combination with Doxorubicin (DOX) treatment resulted in up-regulation of coagulation factor X (FX) in lung interstitial macrophages. Targeting activated FX (FXa) using FXa inhibitor or F10 gene knockdown reduced pro-metastatic effect of chemotherapy-triggered host response. Together, these studies suggest a novel mechanism for chemotherapy induced metastasis via the host response-induced accumulation of monocytes/macrophages and interplay between coagulation and inflammation in the lungs.

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Wu, C., Zhong, Q., Shrestha, R., Wang, J., Hu, X., Li, H., Rouchka, E. C., Yan, J., DING, C.. 2022-12-10. Reactive myelopoiesis and FX-expressing monocyte-derived macrophages triggered by chemotherapy promote cancer lung metastasis. https://doi.org/10.1101/2022.12.07.519466

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