Metabolic reprogramming during spontaneus mammary tumor development and progression in HER2/neu transgenic mice: a role for endogenus type I Interferon

Metabolic reprogramming during spontaneous mammary tumor development and progression in HER2/neu transgenic mice: a role for endogenous type I Interferon Metabolic reprogramming was linked to the major hallmarks of cancer, including tumor development, progression and therapy resistance. Our study aims to identify, by non invasive in vivo MRS and ex vivo high resolution (HR)-MRS, the metabolic changes involved in spontaneous, oncogene-driven carcinogenesis occurring in Her2/neu transgenic mice, with particular focus on the role of endogenous type I IFN (IFN-I). Our group reported that the lack of endogenous IFN-I system significantly affects Her2/neu carcinogenesis (Castiello et al, 2018). Since this phenomenon was not related to the known immunomodulatory properties of these cytokines, we investigated whether the possible reshaping of metabolic pathways was involved. Both in vivo MRS and ex vivo high resolution (HR)-MRS revealed that normal (non-tumoral) mammary glands of mice lacking a functional endogenous IFN-I (IFNARI-/-) had increased fatty acids concentration with respect to the wild type counterpart. This result paralleled the observation of specific trascriptomic profiles in IFNARI-/- normal mammary glands, that exhibited decreased expression of genes involved in OXPHOS and mitochondrial activity and increased expression of Sterol regulatory element-binding proteins, a known regulator of fatty acids biosynthesis and an independent prognostic marker in breast cancer. Interestingly, a trend in fatty acids increase could be also observed in Her2+ early tumor lesions, but not in l bigger tumor masses (>500 um3) spontaneously developed in IFNARI-/- mice. HR-MRS analyses of aqueous metabolites revealed that, as expected, the metabolic fingerprint of Her2+ tumors lesions of all sizes was significantly different from normal mammary glands in both IFNARI+/+ and IFNARI-/- mice. Nevertheless, the impact of the lack of endogenous IFN-I could be more clearly observed in early stage Her2+ tumors. The alterations in myo-inositol and gluthathione concentrations observed in IFNARI-/- tumors suggest that endogenous IFN-I may exert its antitumor activity by affecting key metabolic regulators of tumor cells proliferation. Our study provide the first evidence that endogenous IFN-I is involved in metabolic pathways in both normal mammary glands and early phase breast cancer. Further research is needed to unravel the link between these IFN-related metabolic changes and the proliferation advantage of IFNARI-/- breast cancer cells.