Les proteïnes regulades per glucosa acoblen la reprogramació metabòlica i l’anèrgia tumoral en la progressió metastàtica del càncer de mama

Student thesis: Doctoral thesis

Abstract

The development of the metastatic capacity is owed to the acquisition of specific features that accompany the tumoral cell during the tumoral progression, in the local microenvironment or in distant places. Our group has focused on the identification of proteins that take part in the pathogenesis of the organ-specificity of breast cancer metastasis (1,2,3). We based our study on previous genomic and proteomic results, which showed an over-expression of ERp57 in cells metastatic to bone. We analyzed the organ-specificity of this functional phenotype and its implication in the pathogenesis of bone metastasis. The modulation of this protein could favor the metabolic adaptation to the bone, as ERp57 expression is regulated by the low glucose and oxygen levels found in this microenvironment (4). ERp57 over-expression is involved in the failure of immune recognition of bone metastatic cells, hampering the transport of HLA I molecules to the cell membrane and contributing to Golgi retention. On the other hand, ERp57 reorganizes the vimentin cytoskeleton. This fact suggests a role in the mesenchimal-epithelial transition, which is an essential step for the establishment of the metastatic cell in the new organ. ERp57 under-expression blocks bone metastasis formation suggesting the importance of this protein in the metabolic reprogramming that mediates bone metastatic breast cancer cells adaptation. The combination of Raman spectroscopy (RS) with multivariate analysis techniques has provided a powerful quantitative method for the discrimination of metastatic phenotypes based on metabolic features (5). RS allowed us to distinguish a lipid phenotype associated to the organ-specificity of the metastasis. The determination of total fatty acids or TFA band (2845 cm-1) and total unsaturated fatty acids or TUFA band (3015 cm-1) could distinguish breast cancer cells with the ability to metastasize to bone from those metastatic to brain or lung. The analysis of patients’ genomic data confirmed this phenotype, showing an over-expression of genes related to lipid metabolism in breast cancer brain metastasis. These cells present an organ-specific increase in lipid synthesis and in saturated fatty acids, as well as an increase in the lipid oxidative capacity. This phenotype confers a greater survival advantage in hypoglycemic conditions. Autophagy collaborates with these processes facilitating the degradation of misfolded proteins and providing intermediaries for the Krebs cycle. Finally, studies of morphology and mitochondrial dynamics confirm the metabolic data and they suggest that these features could be a consequence of the differential expression of proteins that regulate the mitochondrion in each microenvironment. These findings point to new therapeutic options to fight against metastatic progression in breast cancer.
Date of Award29 Jul 2013
Original languageCatalan
Awarding Institution
  • Universitat Autònoma de Barcelona (UAB)
SupervisorCarles Arus Caralto (Director) & Àngels Sierra (Director)

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