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Oxygen sensing in macrophages: implications for cancer and ischemia

Final Report Summary - OXYMO (Oxygen sensing in macrophages: implications for cancer and ischemia)

Initially focusing on vascular biology, my research led to the characterization of a new endothelial cell phenotype during the perfusion of hypoxic tissues (Mazzone et al., Cell, 2009; Leite de Oliveira et al., Cancer Cell, 2012). From there, with the support of the ERC Starting Grant, my team has mainly studied the response of inflammatory cells to hypoxia (or to a cytokine surge) in order to restore blood flow in conditions such as cancer and ischemia (Rolny et al., Cancer Cell, 2011; Casazza et al., Cancer Cell, 2013; Wenes et al., Cell Metabolism, 2016; Takeda et al., Nature, 2011; Hamm et al., EMBO Mol Med, 2013). We have been pioneering the concept that localization of tumor-associated macrophages (TAMs) is determinant for their immune phenotype and for the anti-tumor T cell response (Casazza et al., Cancer Cell, 2013; Casazza & Mazzone, Oncoimmunology, 2014), and we have shown that some of these inflammatory fingerprints can be exploited for disease detection and follow-up in cancer patients or can be tackled to improve disease response to targeted therapies (Hamm et al., Gut, 2016; Finisguerra et al., Nature, 2015). At the metastatic site, we discovered an unprecedented anti-metastatic function of macrophages, that by hindering hypoxia-induced angiogenesis, are actinng as gate-keepers of metastatic growth (Celus et al., Cell Reports, 2017). More recently, we found that TAMs encountering hypoxic regions heavily adapt their metabolism; consequently, they will enter in metabolic competition with other stromal components and this will affect their functions (Wenes et al., Cell Metabolism, 2016). Similarly, cancer cells under glucose, oxygen deprivation or stress damage (such as upon chemotherapy) overcome cell death by remodeling their metabolic and oxygen-sensing machinery (Di Conza et al., 2017a; Di Conza et al., 20017b, Deschoemaeker et al., EMBO Mol Med, 2015). Overall, this knowledge on tumor inflammation, not only has underpinned important biology, but led us towards innovative possibilities for cancer diagnostics and therapeutics.