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Menendez J.A.,Catalan Institute of Oncology Girona ICO Girona | Menendez J.A.,Girona Biomedical Research Institute IDIBGI | Alarco n T.,Computational and Mathematical Biology Research Group
Frontiers in Oncology | Year: 2014

The acquisition of and departure from stemness in cancer tissues might not only be hardwired by genetic controllers, but also by the pivotal regulatory role of the cellular metabotype, which may act as a "starter dough" for cancer stemness traits. We have coined the term metabostemness to refer to the metabolic parameters causally controlling or functionally substituting the epitranscriptional orchestration of the genetic reprogramming that redirects normal and tumor cells toward less-differentiated CSC cellular states. Certain metabotypic alterations might operate as pivotal molecular events rendering a cell of origin susceptible to epigenetic rewiring required for the acquisition of aberrant stemness and, concurrently, of refractoriness to differentiation. The metabostemness attribute can remove, diminish, or modify the nature of molecular barriers present in Waddington's epigenetic landscapes, thus allowing differentiated cells to more easily (re)-enter into CSC cellular macrostates. Activation of the metabostemness trait can poise cells with chromatin states competent for rapid dedifferentiation while concomitantly setting the idoneous metabolic stage for later reprogramming stimuli to finish the journey from non-cancerous into tumor-initiating cells. Because only a few permitted metabotypes will be compatible with the operational properties owned by CSC cellular states, the metabostemness property provides a new framework through which to pharmacologically resolve the apparently impossible problem of discovering drugs aimed to target the molecular biology of the cancer stemness itself. We are embarking on one of the cancer field's biggest challenges, namely the discovery of the key metabolic features and the elite metabolites that influence chromatin structure and epigenetic circuits in charge of CSC reprogramming and the incorporation of novel metaboloepigenetic strategies that can effectively hamper cancer initiation and progression at the stem cell level. © 2014 Menendez and Alarco´n.

Fernndez-Real J.M.,CIBER ISCIII | Fernndez-Real J.M.,Girona Biomedical Research Institute IDIBGI | Menendez J.A.,Girona Biomedical Research Institute IDIBGI | Menendez J.A.,Catalan Institute of Oncology Girona ICO Girona | And 7 more authors.
Nutrition and Metabolism | Year: 2010

Background. HER2/neu is a member of the epidermal growth factor receptor family easily detectable in the serum of cancer patients. We aimed to evaluate circulating HER-2 concentrations in association with insulin resistance in healthy and obese subjects. Methods. Insulin sensitivity (minimal model) and serum HER-2 concentrations were evaluated in a cross sectional study in men (cohort 1, n = 167) and longitudinally after weight loss in obese subjects (cohort 2, n = 30). Results. Serum HER-2 concentrations were positively associated with BMI and waist circumference (both r = 0.18, p = 0.02), post-load glucose (r = 0.28, p = 0.001) and fasting triglycerides (r = 0.26, p = 0.001); and negatively associated with insulin sensitivity (r = -0.29, p = 0.002, n = 109). Subjects with type 2 diabetes showed significantly increased soluble serum HER-2 concentrations. In different multivariate regression models, fasting triglycerides emerged as the factor that independently contributed to 10-11% of serum HER-2 variance. Serum HER-2 concentrations correlated significantly with fasting triglycerides and insulin sensitivity index in subjects from cohort 2. Weight loss led to a significant decrease of serum HER-2 concentrations. The change in serum HER-2 concentrations were significantly associated with the change in percent body fat and fasting triglycerides in young (below the median age of the cohort) subjects. Conclusions. Serum HER-2 concentrations might be implicated in the pathophysiology of insulin resistance and associated comorbidities. © 2010 Fernndez-Real et al; licensee BioMed Central Ltd.

Cufi S.,Catalan Institute of Oncology Girona ICO Girona | Cufi S.,Girona Biomedical Research Institute IDIBGI | Vazquez-Martin A.,Catalan Institute of Oncology Girona ICO Girona | Vazquez-Martin A.,Girona Biomedical Research Institute IDIBGI | And 9 more authors.
Oncotarget | Year: 2012

The autophagic process, which can facilitate breast cancer resistance to endocrine, cytotoxic, and molecularly targeted agents, is mainly regulated at the post-translational level. Although recent studies have suggested a possible transcriptome regulation of the autophagic genes, little is known about either the analysis tools that can be applied or the functional importance of putative candidate genes emerging from autophagy-dedicated transcriptome studies. In this context, we evaluated whether the constitutive activation of the autophagy machinery, as revealed by a transcriptome analysis using an autophagy-focused polymerase chain reaction (PCR) array, might allow for the identification of novel autophagy-specific biomarkers for intrinsic (primary) resistance to HER2-targeted therapies. Quantitative real-time PCR (qRT-PCR)-based profiling of 84 genes involved in autophagy revealed that, when compared to trastuzumab-sensitive SKBR3 cells, the positive regulator of autophagic vesicle formation ATG12 (autophagy-related gene 12) was the most differentially up-regulated gene in JIMT1 cells, a model of intrinsic cross-resistance to trastuzumab and other HER1/2-targeting drugs. An analysis of the transcriptional status of ATG12 in > 50 breast cancer cell lines suggested that the ATG12 transcript is commonly upregulated in trastuzumab-unresponsive HER2-overexpressing breast cancer cells. A lentiviral-delivered small hairpin RNA stable knockdown of the ATG12 gene fully suppressed the refractoriness of JIMT1 cells to trastuzumab, erlotinib, gefitinib, and lapatinib in vitro. ATG12 silencing significantly reduced JIMT1 tumor growth induced by subcutaneous injection in nude mice. Remarkably, the outgrowth of trastuzumab-unresponsive tumors was prevented completely when trastuzumab treatment was administered in an ATG12-silenced genetic background. We demonstrate for the first time the usefulness of low-density, autophagy-dedicated qRT-PCR-based platforms for monitoring primary resistance to HER2-targeted therapies by transcriptionally screening the autophagy interactome. The degree of predictive accuracy warrants further investigation in the clinical situation. © Cufi et al.

Corominas-Faja B.,Catalan Institute of Oncology Girona ICO Girona | Corominas-Faja B.,Girona Biomedical Research Institute IDIBGI | Cufi S.,Catalan Institute of Oncology Girona ICO Girona | Cufi S.,Girona Biomedical Research Institute IDIBGI | And 15 more authors.
Cell Cycle | Year: 2013

Energy metabolism plasticity enables stemness programs during the reprogramming of somatic cells to an induced pluripotent stem cell (iPSC) state. This relationship may introduce a new era in the understanding of Warburg's theory on the metabolic origin of cancer at the level of cancer stem cells (CSCs). Here, we used Yamanaka's stem cell technology in an attempt to create stable CSC research lines in which to dissect the transcriptional control of mTO R - the master switch of cellular catabolism and anabolism - in CSC-like states. The rare colonies with iPSC-like morphology, obtained following the viral transduction of the Oct4, Sox2, Klf4, and c-Myc (OSKM) stemness factors into MCF-7 luminal-like breast cancer cells (MCF-7/Rep), demonstrated an intermediate state between cancer cells and bona fide iPSCs. MCF-7/Rep cells notably overexpressed SOX2 and stage-specific embryonic antigen (SSEA)-4 proteins; however, other stemness-related markers (OCT4, NANOG, SSEA-1, TRA-1-60, and TRA-1-81) were found at low to moderate levels. The transcriptional analyses of OSKM factors confirmed the strong but unique reactivation of the endogenous Sox2 stemness gene accompanied by the silencing of the exogenous Sox2 transgene in MCF-7/Rep cells. Some but not all MCF-7/Rep cells acquired strong alkaline phosphatase (AP) activity compared with MCF-7 parental cells. SOX2-overexpressing MCF-7/Rep cells contained drastically higher percentages of CD44+ and ALDEFLUOR-stained ALDHbright cells than MCF-7 parental cells. The overlap between differentially expressed mTO R signaling-related genes in 3 different SOX2-overexpressing CSC-like cell lines revealed a notable downregulation of 3 genes, PRKAA1 (which codes for the catalytic α 1 subunit of AMPK), DDIT4/REDD1 (a stress response gene that operates as a negative regulator of mTO R), and DEPTOR (a naturally occurring endogenous inhibitor of mTO R activity). The insulin-receptor gene (INSR) was differentially upregulated in MCF-7/Rep cells. Consistent with the downregulation of AMPK expression, immunoblotting procedures confirmed upregulation of p70S6K and increased phosphorylation of mTO R in Sox2-overexpressing CSC-like cell populations. Using an in vitro model of the de novo generation of CSC-like states through the nuclear reprogramming of an established breast cancer cell line, we reveal that the transcriptional suppression of mTO R repressors is an intrinsic process occurring during the acquisition of CSC-like properties by differentiated populations of luminal-like breast cancer cells. This approach may provide a new path for obtaining information about preventing the appearance of CSCs through the modulation of the AMPK/mTO R pathway. © 2013 Landes Bioscience.

Vazquez-Martin A.,Catalan Institute of Oncology Girona ICO Girona | Cufi S.,Catalan Institute of Oncology Girona ICO Girona | Oliveras-Ferraros C.,Catalan Institute of Oncology Girona ICO Girona | Menendez J.A.,Catalan Institute of Oncology Girona ICO Girona
Cell Cycle | Year: 2011

Raptor is the key scaffolding protein that recruits mTOR substrates to rapamycin-sensitive mTOR complex 1 (mTORC1), a molecular integrator of mitogenic and nutrient/energy environmental inputs into protein translation and cell growth. Although Raptor phosphorylation on various sites is pivotal in the regulation of mTORC1 activity, it remains to be elucidated whether site-specific phosphorylation differentially distributes Raptor to unique subcellular compartments. When exploring the spatio-temporal cell cycle-dynamics of six different phospho (P)-Raptor isoforms (thr 706, Ser 722, Ser 863, Ser 792 and Ser 877), a number of remarkable events differentially defined a topological resetting of P-Raptor Thr706 on interphasic and mitotic chromosomes. In interphase nuclei, P-Raptor Thr706 co-localized with fibrillarin, a component of the nucleolar small nuclear ribonucleoprotein particle, as well as with RNA polymerase I, the enzyme that transcribes nucleolar rRNA. Upon actinomycin D-induced nucleolar segregation and disaggregation, P-Raptor Thr706 was excluded from nucleolus to accumulate at discrete nucleoplasmic bodies. During mitosis, CDK1 inhibition-induced premature assembly of nucleoli relocated fibrillarin to the surrounding regions of chromosomal-associated P-Raptor Thr706, suggesting that a sub-population of mitotic P-Raptor Thr706 remained targeted at chromosomal loops of rDNA or nuclear organizer regions (NORs). At the end of mitosis and cytokinesis, when re-assembly of incipient nucleoli begins upon NORs activation of rDNA transcription, fibrillarin spatially reorganized with P-Raptor Thr706 to give rise to daughter nucleoli. treatment with IGF1 exclusively hyperactivated nuclear P-Raptor Ser706 and concomitantly promoted Ser 2481-autophosphorylation of mTOR, which monitors mTORC1-associated catalytic activity. Nucleolar- and NOR-associated P-Raptor Ser706 may physically link mTORC1 signaling to ever-growing nucleolus plurifunctionality including ribosome biogenesis, cell stress sensor and cell cycle/aging control. © 2011 Landes Bioscience.

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