Hormone-Independent Mouse Mammary Adenocarcinomas with Different Metastatic Potential Exhibit Different Metabolic Signatures

resumo

The metabolic characteristics of metastatic and non-metastatic breast carcinomas remain poorly studied. In this work, untargeted Nuclear Magnetic Resonance (NMR) metabolomics was used to compare two medroxyprogesterone acetate (MPA)-induced mammary carcinomas lines with different metastatic abilities. Different metabolic signatures distinguished the non-metastatic (59-2-HI) and the metastatic (C7-2-HI) lines, with glucose, amino acid metabolism, nucleotide metabolism and lipid metabolism as the major affected pathways. Non-metastatic tumours appeared to be characterised by: (a) reduced glycolysis and tricarboxylic acid cycle (TCA) activities, possibly resulting in slower NADH biosynthesis and reduced mitochondrial transport chain activity and ATP synthesis; (b) glutamate accumulation possibly related to reduced glutathione activity and reduced mTORC1 activity; and (c) a clear shift to lower phosphoscholine/glycerophosphocholine ratios and sphingomyelin levels. Within each tumour line, metabolic profiles also differed significantly between tumours (i.e., mice). Metastatic tumours exhibited marked inter-tumour changes in polar compounds, some suggesting different glycolytic capacities. Such tumours also showed larger intra-tumour variations in metabolites involved in nucleotide and cholesterol/fatty acid metabolism, in tandem with less changes in TCA and phospholipid metabolism, compared to non-metastatic tumours. This study shows the valuable contribution of untargeted NMR metabolomics to characterise tumour metabolism, thus opening enticing opportunities to find metabolic markers related to metastatic ability in endocrine breast cancer.

palavras-chave

BREAST-CANCER CELLS; MASS-SPECTROMETRY; PHOSPHOLIPID PROFILES; GLUTAMINE-METABOLISM; TUMOR HETEROGENEITY; EXPRESSION; MRS; REVEALS; SAMPLES; PATHWAY

categoria

Biochemistry & Molecular Biology

autores

Bispo, D; Fabris, V; Lamb, CA; Lanari, C; Helguero, LA; Gil, AM

Grupos

G5 - Materiais Biomiméticos, Biológicos e Vivos

Projectos

CICECO - Aveiro Institute of Materials (UID/CTM/50011/2019)

Rede Nacional de Ressonância Magnética Nuclear (PTNMR)

A Metabolomics-guided Bioreactor for Improved Engineered Bone Implants (BioImplant)

agradecimentos

This work was developed within the scope of CICECO-Aveiro Institute of Materials, FCT UID/CTM/50011/2019 and POCI-01-0145-FEDER-007679, financed by national funds through the FCT/MCTES. AMG acknowledges the Portuguese National NMR Network (PTNMR), as the NMR equipment is part of such network, partially supported by Infrastructure Project Nffi 022161, co-financed by FEDER through COMPETE 2020, POCI and PORL and the Portuguese Foundation for Science and Technology (FCT) through PIDDAC. The authors also acknowledge financial support from FCT through projects UID/BIM/04501/2019, UID/BIM/04501/2020 and POCI-01-0145-FEDER-007628 (LH); Integrated Programme CENTRO-01-0145-FEDER-000003 (LH), through project POCI-01-0145-FEDER-028835; PTDC/BTM-ORG/28835/2017, co-funded by the COMPETE 2020 program and European Union fund FEDER. DB is grateful for grants within the ERC-2014-AdG-669858 project and the FCT-SPQ (Portuguese Chemical Society)/Periodic Table protocol.