Daniela Gaglio

Daniela Gaglio
Italian National Research Council | CNR · Institute of Molecular Bioimaging and Physiology IBFM

About

60
Publications
8,618
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1,217
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Introduction
Skills and Expertise
Additional affiliations
May 2009 - July 2009
Massachusetts Institute of Technology
Position
  • PhD Student
Description
  • Research in Cancer cell metabolism by metabolomics approaches using stable isotope tracers and mass spectrometry, to quantify metabolic fluxes in cells.

Publications

Publications (60)
Article
Full-text available
Cyclin-dependent kinase 12 (CDK12) overexpression is implicated in breast cancer, but whether it has a primary or only a cooperative tumorigenic role is unclear. Here, we show that transgenic CDK12 overexpression in the mouse mammary gland per se is sufficient to drive the emergence of multiple and multifocal tumors, while, in cooperation with know...
Article
Polystyrene is a thermoplastic polymer widely used in commercial products. Like all plastics, polystyrene can be degraded into microplastic and nanoplastic particles and ingested via food chain contamination. Although the ecological impact due to plastic contamination is well known, there are no studies indicating a carcinogenic potential of polyst...
Article
Full-text available
Metabolism is directly and indirectly fine-tuned by a complex web of interacting regulatory mechanisms that fall into two major classes. On the one hand, the expression level of the catalyzing enzyme sets the maximal theoretical flux level (i.e., the net rate of the reaction) for each enzyme-controlled reaction. On the other hand, metabolic regulat...
Article
Full-text available
Rewiring glucose metabolism toward aerobic glycolysis provides cancer cells with a rapid generation of pyruvate, ATP, and NADH, while pyruvate oxidation to lactate guarantees refueling of oxidized NAD+ to sustain glycolysis. CtPB2, an NADH-dependent transcriptional co-regulator, has been proposed to work as an NADH sensor, linking metabolism to epi...
Preprint
Full-text available
Metabolism is directly and indirectly fine-tuned by a complex web of interacting regulatory mechanisms that fall into two major classes. First, metabolic regulation controls metabolic fluxes (i.e., the rate of individual metabolic reactions) through the interactions of metabolites (substrates, cofactors, allosteric modulators) with the responsible...
Article
Full-text available
The relevant role of pentose phosphate pathway (PPP) in cancer metabolic reprogramming has been usually outlined by studying glucose-6-phosphate dehydrogenase (G6PD). However, recent evidence suggests an unexpected role for a less characterized PPP, triggered by hexose-6-phosphate dehydrogenase (H6PD) within the endoplasmic reticulum (ER). Studying...
Article
Full-text available
Liver cancer is one of the most common cancer worldwide with a high mortality. Methionine is an essential amino acid required for normal development and cell growth, is mainly metabolized in the liver, and its role as an anti-cancer supplement is still controversial. Here, we evaluate the effects of methionine supplementation in liver cancer cells....
Article
Full-text available
Background: Rewiring of metabolism induced by oncogenic K-Ras in cancer cells involves both glucose and glutamine utilization sustaining enhanced, unrestricted growth. The development of effective anti-cancer treatments targeting metabolism may be facilitated by the identification and rational combinatorial targeting of metabolic pathways. Method...
Article
Full-text available
Metabolomics is a rapidly expanding technology that finds increasing application in a variety of fields, form metabolic disorders to cancer, from nutrition and wellness to design and optimization of cell factories. The integration of metabolic snapshots with metabolic fluxes, physiological readouts, metabolic models, and knowledge-informed Artifici...
Article
Full-text available
Neuroinflammation, a hallmark of chronic neurodegenerative disorders, is characterized by sustained glial activation and the generation of an inflammatory loop, through the release of cytokines and other neurotoxic mediators that cause oxidative stress and limit functional repair of brain parenchyma. Dietary antioxidants may protect against neurode...
Article
Full-text available
In breast cancer (BC) care, radiotherapy is considered an efficient treatment, prescribed both for controlling localized tumors or as a therapeutic option in case of inoperable, incompletely resected or recurrent tumors. However, approximately 90% of BC-related deaths are due to the metastatic tumor progression. Then, it is strongly desirable to im...
Article
Full-text available
Neuronal differentiation involves extensive modification of biochemical and morphological properties to meet novel functional requirements. Reorganization of the mitochondrial network to match the higher energy demand plays a pivotal role in this process. Mechanisms of neuronal differentiation in response to nerve growth factor (NGF) have been larg...
Article
Full-text available
Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with poor survival. Cytoreduction in association with radiotherapy and temozolomide (TMZ) is the standard therapy, but response is heterogeneous and life expectancy is limited. The combined use of chemotherapeutic agents with drugs targeting cell metabolism is becoming an inte...
Article
Full-text available
Cancer cells share several metabolic traits, including aerobic production of lactate from glucose (Warburg effect), extensive glutamine utilization and impaired mitochondrial electron flow. It is still unclear how these metabolic rearrangements, which may involve different molecular events in different cells, contribute to a selective advantage for...
Data
Analytical computations supporting simulation results in Fig 6. For different possible flux routes (table rows), the P/O ratio (column 8) of as well as the moles of acetyl-CoA deriving form one mole of substrate (column 10) following the considered route is computed. In some cases, the row indicates the difference between the computations of two po...
Data
ENGRO1 SBML model. Excel file of the model compliant with: RAVEN Toolbox and FAME. (XML)
Data
ENGRO1 SVG map. Scalable Vector Graphics image of the model, compliant with the software FAME. (SVG)
Data
ENGRO1 biomass optimization for different boundary conditions (supplement to Fig 4). All data derive from Flux Variability Analysis in experiments that maximize biomass production. All reported fluxes do not show variability in optimal solutions. All glucose available is always fully consumed in these simulations. A) Growth rate (z-axis) and oxygen...
Data
Interplay among the sub-networks showing alternative flux patterns in Fig 5. The first sub-network (shaded polygon, with the exception of pyruvate carboxylase) includes PEP carboxykinase; pyruvate kinase, NADP and NAD dependent malic enzyme and malate dehydrogenase. Because the TCA cycle is working in a non-cyclic mode, this set of reactions allows...
Data
Experimental raw data. Raw data (enzyme assays, growth curves, metabolomics) used to build graphs in Fig 3. (XLS)
Data
Supplemental text. Biochemical interpretation of experimental results. (PDF)
Data
ENGRO1 excel model. Excel file of the model compliant with the RAVEN Toolbox. (XLS)
Data
Similarity of results obtained when oxygen consumption is modulated by altering either oxygen availability (as in Fig 4) or Complex I capacity (flux upper bound). Note that because of the reaction stoichiometry, Complex I flux is proportionally higher than the corresponding oxygen consumption rate. A-B) Growth rate scaled on glucose availability as...
Data
On why glutamine is the preferred anaplerotic precursor (supplement to Fig 6). A) Maximum and minimum value for lactate secretion across optimal growth solutions according to FVA, as a function of the parameter pROS that emulates the level of production of reactive oxygen species in the respiratory chain (see S1 Supplemental Methods). Glucose avail...
Data
Determination of sample size. A) Standard deviation of the model fluxes (represented with different colors) as a function of the sample size. B) Zoom in on fluxes of panel A with low standard deviations. The fluxes with high standard deviations correspond to those with high variability when running FVA. C) Relative standard error of the mean of eac...
Data
ENGRO1 flux distribution that maximizes growth at critical O2GR (O2: 38 mM h-1; G: 10 mM h-1; Q: 40 mM h-1). The optimal flux value obtained with FBA, the minimum and maximum value as well as the range size, obtained with FVA, are reported for each reaction. (XLSX)
Data
ENGRO1 flux distribution that maximizes ATP production at critical O2GR (O2: 38 mM h-1; G: 10 mM h-1; Q: 40 mM h-1). The optimal flux value obtained with FBA, the minimum and maximum value as well as the range size, obtained with FVA, are reported for each reaction. (XLSX)
Data
Supplemental methods. Details on ENGRO1 model reconstruction. (PDF)
Article
Full-text available
Oncogenic K-ras is capable to control tumor growth and progression by rewiring cancer metabolism. In vitro NIH-Ras cells convert glucose to lactate and use glutamine to sustain anabolic processes, but their in vivo environmental adaptation and multiple metabolic pathways activation ability is poorly understood. Here, we show that NIH-Ras cancer cel...
Article
The metabolic rearrangements occurring in cancer cells can be effectively investigated with a Systems Biology approach supported by metabolic network modeling. We here present tissue-specific constraint-based core models for three different types of tumors (liver, breast and lung) that serve this purpose. The core models were extracted and manually...
Article
Full-text available
Glutamine utilization promotes enhanced growth of cancer cells. We propose a new concept map of cancer metabolism in which mitochondrial NADH and NADPH, in the presence of a dysfunctional electron transfer chain, promote reductive carboxylation from glutamine. We also discuss why nicotinamide nucleotide transhydrogenase (NNT) is required in vivo fo...
Article
Full-text available
Cell metabolism is the biochemical machinery that provides energy and building blocks to sustain life. Understanding its fine regulation is of pivotal relevance in several fields, from metabolic engineering applications to the treatment of metabolic disorders and cancer. Sophisticated computational approaches are needed to unravel the complexity of...
Article
Full-text available
An extensive rewiring of cell metabolism supports enhanced proliferation in cancer cells. We propose a systems level approach to describe this phenomenon based on Flux Balance Analysis (FBA). The approach does not explicit a cell biomass formation reaction to be maximized, but takes into account an ensemble of alternative flux distributions that ma...
Article
Despite their different histological and molecular properties, different types of cancers share few essential functional alterations. Some of these cancer hallmarks may easily be studied in in vitro cultures, while others are related to the way in which tumors grow in vivo. According to the systems biology paradigm, complex cellular functions arise...
Article
Full-text available
Systems Biology holds that complex cellular functions are generated as system-level properties endowed with robustness, each involving large networks of molecular determinants, generally identified by "omics" analyses. In this paper we describe four basic cancer cell properties that can easily be investigated in vitro: enhanced proliferation, evasi...
Data
Full-text available
Supplementary figures S1–11, Supplementary Tables S1–4
Article
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Oncogenes such as K-ras mediate cellular and metabolic transformation during tumorigenesis. To analyze K-Ras-dependent metabolic alterations, we employed 13 C metabolic flux analysis (MFA), non-targeted tracer fate detection (NTFD) of 15 N-labeled glutamine, and transcriptomic profiling in mouse fibroblast and human carcinoma cell lines. Stable iso...
Article
Great interest is presently given to the analysis of metabolic changes that take place specifically in cancer cells. In this review we summarize the alterations in glycolysis, glutamine utilization, fatty acid synthesis and mitochondrial function that have been reported to occur in cancer cells and in human tumors. We then propose considering cance...
Data
Initial concentration values in both wild type and off state.
Data
Set of kinetic equations (a) and Ordinary Differential Equations (ODE) (b) describing the mathematical model of the G1/S transition.
Data
Rate constants in the wild type condition. In bold are the parameters altered in the off state (in parentheses are reported the values for the off state).
Article
Full-text available
The cell cycle is a complex process that allows eukaryotic cells to replicate chromosomal DNA and partition it into two daughter cells. A relevant regulatory step is in the G0/G1 phase, a point called the restriction (R) point where intracellular and extracellular signals are monitored and integrated.Subcellular localization of cell cycle proteins...
Data
Analysis of glutamine concentration, along a time course of 96 h, of normal (blue diamond) and transformed (red square) cells plated in 4 mM (A) and 0.5 mM (B) initial glutamine availability. (1.25 MB TIF)
Data
Proliferation and cell cycle analysis of lower density plated cells. (8.16 MB TIF)
Data
p27kip1 localization in BrdU positive cells and p21waf1 expression in normal and transformed cells. (2.65 MB TIF)
Data
Glutamine availability effect on total cellular proteins as detected by Gel-Code Blue Comassie staining. (4.43 MB TIF)
Data
Glucose depletion induces a strong cell proliferation arrest in K-ras transformed mouse fibroblasts. (1.15 MB TIF)
Data
Cdk2 and Cdk4 proteins expression is more stable in transformed cells. (1.56 MB TIF)
Data
Proliferation ability and time of re-entry upon serum starvation and release in cells grown in 4 mM glutamine. (2.68 MB TIF)
Article
Full-text available
Background: Oncogene activation plays a role in metabolic reprogramming of cancer cells. We have previously shown that K-ras transformed fibroblasts have a stronger dependence on glycolysis and a reduced oxidative phosphorylation ability as compared to their normal counterparts. Another metabolic adaptation of cancer cells, that has long been esta...
Article
Full-text available
Through its ability to regulate the activity of a large number of transcription factors, the Ras pathway is able to control several transcriptional programs leading to proliferation, differentiation, metabolism, cytoskeletal reorganization and immune response. Cyclic AMP (cAMP) is a ubiquitous intracellular second messenger whose major intracellula...
Article
Full-text available
K-ras transformed fibroblasts have been shown to have a stronger dependence from glycolysis, reduced oxidative phosphorylation ability and a fragility towards glucose depletion compared to their immortalized, normal counterparts. In this paper, using RNA profiling assays and metabolic perturbations, we report changes in expression of genes encoding...