GRP94 Is Involved in the Lipid Phenotype of Brain Metastatic Cells

• Published in: International journal of molecular sciences 2019-08, Vol.20 (16), p.3883
• Main Authors: Santana-Codina, Naiara, Marcé-Grau, Anna, Muixí, Laia, Nieva, Claudia, Marro, Mónica, Sebastián, David, Muñoz, Juan Pablo, Zorzano, Antonio, Sierra, Angels
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Brain - metabolism; Brain - pathology; Brain cancer; brain metastasis; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain Neoplasms - secondary; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Cell surface; Cholesterol; Crosstalk; Disease Progression; Endoplasmic reticulum; endoplasmic reticulum stress; Environmental stress; Enzymes; Esterification; Fatty acids; Fatty Acids - analysis; Fatty Acids - metabolism; Female; Fluorescent indicators; Gene expression; Genotype & phenotype; GRP94; Heat shock proteins; HSP70 Heat-Shock Proteins - analysis; HSP70 Heat-Shock Proteins - metabolism; Humans; Immune system; Integrins; Invasiveness; Lipid metabolism; Lipids; Malignancy; Medical prognosis; Membrane proteins; Membrane Proteins - analysis; Membrane Proteins - metabolism; Metabolism; Metastases; Metastasis; Mice, Nude; Phenotypes; Principal components analysis; Proteins; Radiation tolerance; Stem cells; Sterols; Toll-like receptors; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20163883

Metabolic adaptation may happen in response to the pressure exerted by the microenvironment and is a key step in survival of metastatic cells. Brain metastasis occurs as a consequence of the systemic dissemination of tumor cells, a fact that correlates with poor prognosis and high morbidity due to the difficulty in identifying biomarkers that allow a more targeted therapy. Previously, we performed transcriptomic analysis of human breast cancer patient samples and evaluated the differential expression of genes in brain metastasis (BrM) compared to lung, bone and liver metastasis. Our network approach identified upregulation of glucose-regulated protein 94 (GRP94) as well as proteins related to synthesis of fatty acids (FA) in BrM. Here we report that BrM cells show an increase in FA content and decreased saturation with regard to parental cells measured by Raman spectroscopy that differentiate BrM from other metastases. Moreover, BrM cells exerted a high ability to oxidize FA and compensate hypoglycemic stress due to an overexpression of proteins involved in FA synthesis and degradation (SREBP-1, LXRα, ACOT7). GRP94 ablation restored glucose dependence, down-regulated ACOT7 and SREBP-1 and decreased tumorigenicity in vivo. In conclusion, GRP94 is required for the metabolic stress survival of BrM cells, and it might act as a modulator of lipid metabolism to favor BrM progression.