Wednesday, April 2, 2025
4/2/2025
Mitochondrial regulation of chemotherapy-induced reactive myelopoiesis and pro-metastatic effects - Recent studies and our preliminary data highlight the importance of myelopoiesis in the chemotherapy induced accumulation of immunosuppressive myeloid cells. Growing evidence also demonstrates the ability of hematopoietic stem and progenitor cells (HSPCs) to sense inflammation, ultimately regulating HSPC proliferation and differentiation via metabolic alterations. It’s known that mitochondrial oxidative phosphorylation (OXPHOS) results in an increase of reactive oxygen species (ROS) production in HSPCs. However, our understanding of inflammation, metabolic alterations of HSPCs, and monocyte development is still limited. Current antioxidant strategies are not clinically effective. Finding novel targets could provide better therapeutic efficacy for combination therapy with chemotherapy. Mitochondria are the main source of ROS and are highly dynamic through the fission and fusion events, and dynamin-related protein 1 (Drp1) is an essential mediator of mitochondrial fission that elicits excessive ROS production. Importantly, targeting of excessive mitochondrial fission can regulate hematopoiesis via the mechanisms beyond ROS. The objective of this project is to determine whether mitochondrial ROS and Drp1 mediated HSPC mitochondria fission control chemotherapy induced reactive myelopoiesis and pro-metastatic effect. We hypothesize that chemotherapy induces reactive myelopoiesis by enhanced ROS production and Drp1- mediated mitochondrial fission in HSPCs, which drive the expansion of pro-metastatic monocytes. Further, targeting of mtROS or Drp1 reduces chemotherapy-induced metastases by regulating reactive myelopoiesis and monocyte phenotype. We will test our hypothesis by completing the following two specific aims: (1) Determine chemotherapy induced mitochondrial metabolism in HSPCs and phenotypic changes of monocytes, and (2) Determine whether targeting of Drp1 dependent mitochondrial fission reduces chemotherapy induced pro-metastatic effect. The proposed study is significant, because it will reveal a novel mechanism by which chemotherapy induces HSPC mitochondrial fission leading reactive myelopoiesis and pro-metastatic monocyte development. The discovery of role for mitochondrial fission in HSPCs after chemotherapy will stimulate new approach to improve anti-tumor efficacy of conventional chemotherapy.
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