Girona Biomedical Research Institute IDIBGI

Girona, Spain

Girona Biomedical Research Institute IDIBGI

Girona, Spain

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Bosch-Barrera J.,Catalan Institute of Nanoscience and Nanotechnology | Bosch-Barrera J.,Girona Biomedical Research Institute IDIBGI | Menendez J.A.,Girona Biomedical Research Institute IDIBGI | Menendez J.A.,Catalan Institute of Nanoscience and Nanotechnology
Cancer Treatment Reviews | Year: 2015

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in many different types of cancer and plays a pivotal role in tumor growth and metastasis. Retrospective studies have established that STAT3 expression or phospho-STAT3 (pSTAT3 or activated STAT3) are poor prognostic markers for breast, colon, prostate and non-small cell lung cancer. Silibinin or silybin is a natural polyphenolic flavonoid which is present in seed extracts of milk thistle (Silybum marianum). Silibinin has been shown to inhibit multiple cancer cell signaling pathways in preclinical models, demonstrating promising anticancer effects in vitro and in vivo. This review summarizes evidence suggesting that silibinin can inhibit pSTAT3 in preclinical cancer models. We also discuss current strategies to overcome the limitations of oral administration of silibinin to cancer patients to translate the bench results to the bed side. Finally, we review the ongoing clinical trials exploring the role of silibinin in cancer. © 2015 Elsevier Ltd.


Cuyas E.,Catalan Institute of Nanoscience and Nanotechnology | Cuyas E.,Girona Biomedical Research Institute IDIBGI | Corominas-Faja B.,Catalan Institute of Nanoscience and Nanotechnology | Corominas-Faja B.,Girona Biomedical Research Institute IDIBGI | And 2 more authors.
Oncotarget | Year: 2014

The metabolic features of cancer stem (CS) cells and the effects of specific nutrients or metabolites on CS cells remain mostly unexplored. A preliminary study to delineate the nutritional phenome of CS cells exploited the landmark observation that upon experimental induction into an epithelial-to-mesenchymal (EMT) transition, the proportion of CS-like cells drastically increases within a breast cancer cell population. EMT-induced CS-like cells (HMLERshEcad) and isogenic parental cells (HMLERshCntrol) were simultaneously screened for their ability to generate energy-rich NADH when cultured in a standardized high-throughput metabolic phenotyping platform comprising >350 wells that were pre-loaded with different carbohydrates/starches, alcohols, fatty acids, ketones, carboxylic acids, amino acids, and bi-amino acids. The generation of "phenetic maps" of the carbon and nitrogen utilization patterns revealed that the acquisition of a CS-like cellular state provided an enhanced ability to utilize additional catabolic fuels, especially under starvation conditions. Crucially, the acquisition of cancer stemness activated a metabolic infrastructure that enabled the vectorial transfer of high-energy nutrients such as glycolysis end products (pyruvate, lactate) and bona fide ketone bodies (β-hydroxybutyrate) from the extracellular microenvironment to support mitochondrial energy production in CS-like cells. Metabolic reprogramming may thus constitute an efficient adaptive strategy through which CS-like cells would rapidly obtain an advantage in hostile conditions such as nutrient starvation following the inhibition of tumor angiogenesis. By understanding how specific nutrients could bioenergetically boost EMT-CS-like phenotypes, "smart foods" or systemic "metabolic nichotherapies" may be tailored to specific nutritional CSC phenomes, whereas high-resolution heavy isotope-labeled nutrient tracking may be developed to monitor the spatiotemporal distribution and functionality of CS-like cells in real time.


Corominas-Faja B.,Catalan Institute of Nanoscience and Nanotechnology | Corominas-Faja B.,Girona Biomedical Research Institute IDIBGI | Cuyas E.,Catalan Institute of Nanoscience and Nanotechnology | Cuyas E.,Girona Biomedical Research Institute IDIBGI | And 6 more authors.
Oncotarget | Year: 2014

Cancer stem cells (CSC) may take advantage of the Warburg effect-induced siphoning of metabolic intermediates into de novo fatty acid biosynthesis to increase self-renewal growth. We examined the anti-CSC effects of the antifungal polyketide soraphen A, a specific inhibitor of the first committed step of lipid biosynthesis catalyzed by acetyl-CoA carboxylase (ACACA). The mammosphere formation capability of MCF-7 cells was reduced following treatment with soraphen A in a dose-dependent manner. MCF-7 cells engineered to overexpress the oncogene HER2 (MCF-7/HER2 cells) were 5-fold more sensitive than MCF-7 parental cells to soraphen A-induced reductions in mammosphere-forming efficiency. Soraphen A treatment notably decreased aldehyde dehydrogenase (ALDH)-positive CSC-like cells and impeded the HER2's ability to increase the ALDH+-stem cell population. The following results confirmed that soraphen A-induced suppression of CSC populations occurred through ACACA-driven lipogenesis: a.) exogenous supplementation with supraphysiological concentrations of oleic acid fully rescued mammosphere formation in the presence of soraphen A and b.) mammosphere cultures of MCF-7 cells with stably silenced expression of the cytosolic isoform ACACA1, which specifically participates in de novo lipogenesis, were mostly refractory to soraphen A treatment. Our findings reveal for the first time that ACACA may constitute a previously unrecognized target for novel anti-breast CSC therapies.


Menendez J.A.,Catalan Institute of Nanoscience and Nanotechnology | Menendez J.A.,Girona Biomedical Research Institute IDIBGI | Alarcon T.,Computational and Mathematical Biology Research Group | Joven J.,Rovira i Virgili University
Cell Cycle | Year: 2014

Oncometabolites are defined as small-molecule components (or enantiomers) of normal metabolism whose accumulation causes signaling dysregulation to establish a milieu that initiates carcinogenesis. In a similar manner, we propose the term "gerometabolites" to refer to small-molecule components of normal metabolism whose depletion causes signaling dysregulation to establish a milieu that drives aging. In an investigation of the pathogenic activities of the currently recognized oncometabolites R(-)-2-hydroxyglutarate (2-HG), fumarate, and succinate, which accumulate due to mutations in isocitrate dehydrogenases (IDH), fumarate hydratase (FH), and succinate dehydrogenase (SDH), respectively, we illustrate the fact that metabolic pseudohypoxia, the accumulation of hypoxia-inducible factor (HIFα) under normoxic conditions, and the subsequent Warburg-like reprogramming that shifts glucose metabolism from the oxidative pathway to aerobic glycolysis are the same mechanisms through which the decline of the "gerometabolite" nicotinamide adenine dinucleotide (NAD)+ reversibly disrupts nuclear-mitochondrial communication and contributes to the decline in mitochondrial function with age. From an evolutionary perspective, it is reasonable to view NAD +-driven mitochondrial homeostasis as a conserved response to changes in energy supplies and oxygen levels. Similarly, the natural ability of 2-HG to significantly alter epigenetics might reflect an evolutionarily ancient role of certain metabolites to signal for elevated glutamine/glutamate metabolism and/or oxygen deficiency. However, when chronically altered, these responses become conserved causes of aging and cancer. Because HIFα-driven pseudohypoxia might drive the overproduction of 2-HG, the intriguing possibility exists that the decline of gerometabolites such as NAD+ could promote the chronic accumulation of oncometabolites in normal cells during aging. If the sole activation of a Warburg-like metabolic reprogramming in normal tissues might be able to significantly increase the endogenous production of bona fide etiological determinants in cancer, such as oncometabolites, this undesirable trade-off between mitochondrial dysfunction and activation of oncometabolites production might then pave the way for the epigenetic initiation of carcinogenesis in a strictly metabolic-dependent manner. Perhaps it is time to definitely adopt the view that aging and aging diseases including cancer are governed by a pivotal regulatory role of metabolic reprogramming in cell fate decisions. © 2014 Landes Bioscience.


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.


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 6 more authors.
Cell Cycle | Year: 2011

The molecular mechanisms used by breast cancer stem cells (BCSCs) to survive and/or maintain their undifferentiated CD44 +CD24 -/low mesenchymal-like antigenic state remain largely unexplored. Autophagy, a key homeostatic process of cytoplasmic degradation and recycling evolved to respond to stress conditions, might be causally fundamental in the biology of BCSCs. Stable and specific knockdown of autophagy-regulatory genes by lentiviral-delivered small hairpin (sh) RNA drastically decreased the number of JIMT-1 epithelial BC cells bearing CD44 +CD24 -/low cell-surface antigens from ∼75% in parental and control (-) shRNA-transduced cells to 26% and 7% in ATG8/LC3 shRNA- and ATG12 shRNA-transduced cells, respectively. Autophagy inhibition notably enhanced transcriptional activation of CD24 gene, potentiating the epithelial-like phenotype of CD44 +CD24 + cells vs. the mesenchymal CD44 +CD24 -/low progeny. EMT-focused Real Time RT-PCR profiling revealed that genetic ablation of autophagy transcriptionally repressed the gene coding for the mesenchymal filament vimentin (VIM). shRNA-driven silencing of the ATG12 gene and disabling the final step in the autophagy pathway by the antimalarial drug chloroquine both prevented TGFβ1-induced accumulation of vimentin in JIMT-1 cells. Knockdown of autophagy-specific genes was sufficient also to increase by up to 11-times the number of CD24 + cells in MDA-MB-231 cells, a BC model of mesenchymal origin that is virtually composed of CD44 +CD24 -/low cells. Chloroquine treatment augmented the number of CD24 + cells and concomitantly reduced constitutive overexpression of vimentin in MDA-MB-231 cells. This is the first report demonstrating that autophagy is mechanistically linked to the maintenance of tumor cells expressing high levels of CD44 and low levels of CD24, which are typical of BCSCs. © 2011 Landes Bioscience.


Menendez J.A.,Catalan Institute of Oncology Girona ICOGirona | Menendez J.A.,Girona Biomedical Research Institute IDIBGi | Joven J.,Rovira i Virgili University
Aging | Year: 2012

The gerosuppressant metformin operates as an efficient inhibitor of the mTOR/S6K1 gerogenic pathway due to its ability to ultimately activate the energy-sensor AMPK. If an aging-related decline in the AMPK sensitivity to cellular stress is a crucial event for mTOR-driven aging and aging-related diseases, including cancer, unraveling new proximal causes through which AMPK activation endows its gerosuppressive effects may offer not only a better understanding of metformin function but also the likely possibility of repositioning our existing gerosuppressant drugs. Here we provide our perspective on recent findings suggesting that de novo biosynthesis of purine nucleotides, which is based on the metabolism of one-carbon compounds, is a new target for metformin's actions at the crossroads of aging and cancer. © Menendez and Joven.


Alonso M.,University of Girona | Castellanos M.,University of Girona | Castellanos M.,Girona Biomedical Research Institute IdIBGi | Besalu E.,University of Girona | And 2 more authors.
Journal of Chromatography A | Year: 2012

Needle trap devices (NTDs) are a relatively new and promising tool for headspace (HS) analysis. In this study, a dynamic HS sampling procedure is evaluated for the determination of volatile organic compounds (VOCs) in whole blood samples. A full factorial design was used to evaluate the influence of the number of cycles and incubation time and it is demonstrated that the controlling factor in the process is the number of cycles. A mathematical model can be used to determine the most appropriate number of cycles required to adsorb a prefixed amount of VOCs present in the HS phase whenever quantitative adsorption is reached in each cycle. Matrix effect is of great importance when complex biological samples, such as blood, are analyzed. The evaluation of the salting out effect showed a significant improvement in the volatilization of VOCs to the HS in this type of matrices. Moreover, a 1:4 (blood:water) dilution is required to obtain quantitative recoveries of the target analytes when external calibration is used. The method developed gives detection limits in the 0.020-0.080μgL -1 range (0.1-0.4μgL -1 range for undiluted blood samples) with appropriate repeatability values (RSD<15% at high level and <23% at LOQ level). Figure of merits of the method can be improved by using a smaller phase ratio (i.e., an increase in the blood volume and a decrease in the HS volume), which lead to lower detection limits, better repeatability values and greater sensibility. Twenty-eight blood samples have been evaluated with the proposed method and the results agree with those indicated in other studies. Benzene was the only target compound that gave significant differences between blood levels detected in volunteer non-smokers and smokers. © 2012 Elsevier B.V.


Verges M.,Girona Biomedical Research Institute IDIBGI | Verges M.,University of Girona
International Review of Cell and Molecular Biology | Year: 2016

Retromer is an evolutionary conserved protein complex required for endosome-to-Golgi retrieval of receptors for lysosomal hydrolases. It is constituted by a heterotrimer encoded by the vacuolar protein sorting (VPS) gene products Vps26, Vps35, and Vps29, which selects cargo, and a dimer of phosphoinositide-binding sorting nexins, which deforms the membrane. Recent progress in the mechanism of retromer assembly and functioning has strengthened the link between sorting at the endosome and cytoskeleton dynamics. Retromer is implicated in endosomal sorting of many cargos and plays an essential role in plant and animal development. Although it is best known for endosome sorting to the trans-Golgi network, it also intervenes in recycling to the plasma membrane. In polarized cells, such as epithelial cells and neurons, retromer may also be utilized for transcytosis and long-range transport. Considerable evidence implicates retromer in establishment and maintenance of cell polarity. That includes sorting of the apical polarity module Crumbs; regulation of retromer function by the basolateral polarity module Scribble; and retromer-dependent recycling of various cargoes to a certain surface domain, thus controlling polarized location and cell homeostasis. Importantly, altered retromer function has been linked to neurodegeneration, such as in Alzheimer's or Parkinson's disease. This review will underline how alterations in retromer localization and function may affect polarized protein transport and polarity establishment, thereby causing developmental defects and disease. © 2016 Elsevier Inc..


Vazquez-Martin A.,University of Franca | Vazquez-Martin A.,Girona Biomedical Research Institute IdIBGi | Oliveras-Ferraros C.,University of Franca | Oliveras-Ferraros C.,Girona Biomedical Research Institute IdIBGi | And 3 more authors.
Breast Cancer Research and Treatment | Year: 2011

We here demonstrate that the anti-diabetic drug metformin interacts synergistically with the anti-HER2 monoclonal antibody trastuzumab (Tzb; Herceptin™) to eliminate stem/progenitor cell populations in HER2-gene-amplified breast carcinoma cells. When using the mam-mosphere culture technique, graded concentrations of single-agent metformin (range 50-1,000 μmol/l) were found to dose-dependently reduce the number of mammospheres formed by SKBR3 (a Tzb-naïve model), SKBR3 TzbR (a model of acquired auto-resistance to Tzb) and JIMT-1 (a model of refractoriness to Tzb and other HER2-targeted therapies ab initio) HER2-overexpressing breast cancer cells. Single-agent Tzb likewise reduced mammosphere-forming efficiency (MSFE) in Tzb-naïve SKBR3 cells, but it failed to significantly decrease MSFE in Tzb-resistant SKBR3 TzbR and JIMT-1 cells. Of note, CD44-overexpressing Tzb-refractory SKBR3 TzbR and JIMT-1 cells retained an exquisite sensitivity to single-agent metformin. Concurrent combination of metformin with Tzb synergistically reduced MSFE as well as the size of mammospheres in Tzb-refractory SKBR3 TzbR and JIMT-1 cells. Flow cytometry analyses confirmed that metformin and Tzb functioned synergistically to down-regulate the percentage of Tzb-refractory JIMT-1 cells displaying the CD44 pos/CD24 neg/low stem/progenitor immunophenotype. Given that MSFE and mammosphere size are indicators of stem self-renewal and progenitor cell proliferation, respectively, our current findings reveal for the first time that: (a) Tzb refractoriness in HER2 overexpressors can be explained in terms of Tzb-resistant/CD44-overexpressing/tumor-initiating stem cells; (b) metformin synergistically interacts with Tzb to suppress self-renewal and proliferation of cancer stem/progenitor cells in HER2-positive carcinomas. © 2011 Springer Science+Business Media, LLC.

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