MNSOD ACETYLATION PROMOTES CANCER STEM CELL PHENOTYPES IN BREAST CANCER

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PROJECT SUMMARY Aggressive phenotypes of breast cancer are characterized by increased capacity of evading immune surveillance and generating metastasis. Our groups recently described that metastatic breast cancer cells expressing high levels of acetylated superoxide dismutase 2 (SOD2K68Ac) accumulate mitochondria-derived reactive oxygen species (mtROS) and promote stabilization of hypoxia-inducible factor 2α (HIF2α), involved tumor aggressiveness. HIF2α also regulates genes associated with immune protection, including the programmed death-ligand 1 (PDL1) that is widely recognized as a molecule eliciting immune evasion in cancer cells. Hence, we propose to investigate (1) if accumulation of SOD2K68Ac promotes PDL1 upregulation via HIF2α in breast cancer cells; (2) if SOD2K68Ac/HIF2α promotes mammary cancer immune evasion and metastasis in vivo using mouse model; and (3) if there is a subgroup of women with breast cancer that exhibits SOD2K68Ac/HIF2α molecular signature correlating with high PDL1 expression and immunotherapy resistance. We expect to identify a new mechanism of cancer immune evasion that can be targeted to improve therapeutic approaches to treat aggressive phenotypes of breast cancer exhibiting SOD2K68Ac molecular signature. The proposed translational research will be conducted by Dr. Coelho under the mentorship of Dr. Marcelo Bonini (primary mentor), Dr. Leonidas Platanias (co-mentor) and Dr. Massimo Cristofanilli (clinical co-mentor). All mentors have exemplary records of scientific achievement, innovation and leadership in the translational pipeline of cancer therapeutics and diagnostics. In addition to the scientific goal of this application, we expect that Dr. Coelho will accomplish a multidisciplinary training in clinical research, leadership, writing and management essential to establish an independent career in cancer immunobiology.