Abstract 131: Neutrophil extracellular trap mediate mitochondrial biogenesis in cancer cells to promote growth of metastases

Abstract

Abstract Neutrophils through the release of neutrophil extracellular traps (NETs) in response to surgical stress were shown to be able to capture circulating cancer cells, and in doing so, support the development of metastatic disease. In addition, NETs persist within the tumor microenvironment long after the surgical stress happens. The exact nature of the NETs-tumor interaction and the role that NETs play in dictating the tumor microenvironment is unclear. In vivo, subcutaneous and liver metastasis models of colorectal and hepatocellular cancer were performed in wild type and PAD4 KO mice that lack the ability to form NETs. In vitro, bioenergetics profiles of both HCC and CRC cancer cells were studied after co-culture with NETs, isolated from human and murine neutrophils. We found a 3-fold decrease in the tumor volume of PAD4 KO mice compared to control mice 3 weeks after tumor injection in both subcutaneous and liver metastatic models. PAD4 KO tumors showed significantly decreased neutrophil infiltration and no NET formation within the tumor compared to WT mice. PAD4 KO tumors had decreased proliferation rates and increased apoptosis. In vitro, stressed cancer cells release stress signals such as cytokines, chemokines, and DAMPs (HMGB1 and histones), that enhanced neutrophil migration towards them and subsequently triggered NET formation. In turn, NETs resulted in a 2-fold increase in the expression of mitochondrial biogenesis regulators in cancer cells. Increase mitochondrial mass was observed when treated cancer cells with NETs. A significant increase mitochondrial oxygen consumption rate (OCR) and ATP levels were observed when compared with DNase treatment. Taken together, we suggest that cancer cells help in recruiting NETs which in turn regulates mitochondrial bioenergetics for tumor growth and metastasis. Citation Format: Hamza Yazdani, Samer Tohme, Eva Roy, Patricia Loughran, Dirk Vander Windth, Hai Huang, Allan Tsung. Neutrophil extracellular trap mediate mitochondrial biogenesis in cancer cells to promote growth of metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 131.