Changes in metabolic patterns during tumor development and progression in HER2/neu spontaneous breast cancer: a role for endogenous type I Interferon

Changes in metabolic patterns during tumor development and progression in HER2/neu spontaneous breast cancer: a role for endogenous type I Interferon In the last decades, cell metabolism emerged as a key factor involved in tumor development, progression and therapy resistance. Our group reported that the disruption of endogenous type I Interferon (IFN-I) system affects spontaneous Her2/neu-driven carcinogenesis through intrinsic control of cancer stem cells (Castiello et al, 2018). In order to investigate whether the possible remodeling of metabolic pathways was involved in this phenomenon, we applied non invasive in vivo MRS and ex vivo high resolution (HR)-MRS to analyze the changes in metabolic profiles occurring in healthy mammary glands and spontaneous tumors developed in Her2/ neu transgenic mice, with particular focus on IFN-I. Both in vivo MRS and ex vivo high resolution (HR)-MRS revealed that, in the absence of a functional endogenous IFN-I (IFNARI-/-), normal (non-tumoral) mammary glands had increased fatty acids concentration with respect to the wild type counterpart. This result paralleled the observation that IFNARI-/- normal mammary glands 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. Interestingly, Her2+ early tumor lesions developed in IFNARI-/- mice also exhibited increased fatty acids content versus wild type mice. In contrast, bigger tumor masses (>500 um3) presented a more dysregulated and less consistent metabolic profile in both groups. As expected, the metabolic fingerprint of Her2+ tumors lesions of all sizes, assessed by HR-MRS analyses of aqueous metabolites, was significantly different from normal mammary glands in IFNARI+/+ and IFNARI-/- mice. Nevertheless, the impact of the lack of endogenous IFN-I could be 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 also by affecting key metabolic regulators of tumor cells proliferation. Our study provide the first evidence that endogenous IFN-I takes part in the regulation of some metabolic pathways occurring in normal mammary glands and affecting early phase of spontaneous breast cancer development. How these metabolic changes eventually provide a proliferation advantage to breast cancer cells is a matter of further investigation.