References of "De Tullio, Pascal"
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See detailTGFBI, an ECM interacting protein, enhances glycolysis and promotes pancreatic cancer cell migration
Costanza, Brunella; Rademaker, Gilles ULiege; Tiamiou, Assia ULiege et al

in International Journal of Cancer (in press)

Pancreatic cancer (PDAC) remains a deadly malignancy with no efficient therapy available up-to-date. Glycolysis is the main provider of energetic substrates to sustain cancer dissemination of PDAC ... [more ▼]

Pancreatic cancer (PDAC) remains a deadly malignancy with no efficient therapy available up-to-date. Glycolysis is the main provider of energetic substrates to sustain cancer dissemination of PDAC. Accordingly, altering the glycolytic pathway is foreseen as a sound approach to trigger pancreatic cancer regression. Here, we show for the first time that high TGFBI expression in PDAC patients is associated with a poor outcome. We demonstrate that, although usually secreted by stromal cells, PDAC cells synthesize and secrete TGFBI in quantity correlated with their migratory capacity. Mechanistically, we show that TGFBI activates FAK signaling pathway through its binding to integrin αVβ5, leading to a significant enhancement of glycolysis and to the acquisition of an invasive phenotype. Finally, we show that TGFBI silencing significantly inhibits PDAC tumor development in a chick chorioallantoic membrane assay model. Our study highlights TGFBI as an oncogenic ECM interacting protein that bears the potential to serve as a target for new anti-PDAC therapeutic strategies. [less ▲]

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See detailMetabolomics as an Innovative Tool for a Personalised Approach to Vascular Disease
De Tullio, Pascal ULiege; Leenders, Justine ULiege; Vega de Ceniga, Melina et al

in European Journal of Vascular and Endovascular Surgery (2019), 57(3), 329

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See detailSelective pharmacological inhibitors of HDAC6 reveal biochemical activity but functional tolerance in cancer models
Depetter, Yves; Geurs, Silke; De Vreese, Rob et al

in International Journal of Cancer (2019)

Our study investigates the biochemical and functional impact of selective histone deacetylase 6 (HDAC6) inhibitors, a promising class of novel therapeutics, in several cancer models. Selective HDAC6 ... [more ▼]

Our study investigates the biochemical and functional impact of selective histone deacetylase 6 (HDAC6) inhibitors, a promising class of novel therapeutics, in several cancer models. Selective HDAC6 inhibitors (Tubathian A, Tubastatin A, Tubacin and Ricolinostat) and a non-selective HDAC inhibitor (Vorinostat) were evaluated on cancer cell lines derived from multiple tumour types in both an in vitro and in vivo setting as potential cancer therapeutics. Selective HDAC6 inhibitors resulted in α-tubulin acetylation with no impact on histone acetylation but failed to show any anti-cancer properties. Only the use of high concentrations of selective HDAC6 inhibitors resulted in co-inhibition of other HDAC enzymes and consequently in reduced growth, migratory and/or invasive activity of cancer cells in vitro as well as in vivo. The specificity of HDAC6 inhibition was confirmed using a CRISPR/Cas9 knockout cell line. Our results suggest that selective HDAC6 inhibitors may fall short as potential single agent anti-cancer drugs and prove that many previous data regarding this promising class of compounds need to be interpreted with great care due to their use in high concentrations resulting in low selectivity and potential off-target effects. [less ▲]

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See detailTwo data pre‑processing workflows to facilitate the discovery of biomarkers by 2D NMR metabolomics
Feraud, Baptiste; Leenders, Justine ULiege; Martineau, Estelle et al

in Metabolomics (2019), 15(63),

Abstract Introduction The pre-processing of analytical data in metabolomics must be considered as a whole to allow the construction of a global and unique object for any further simultaneous data analysis ... [more ▼]

Abstract Introduction The pre-processing of analytical data in metabolomics must be considered as a whole to allow the construction of a global and unique object for any further simultaneous data analysis or multivariate statistical modelling. For 1D 1H-NMR metabolomics experiments, best practices for data pre-processing are well defined, but not yet for 2D experiments (for instance COSY in this paper). Objective By considering the added value of a second dimension, the objective is to propose two workflows dedicated to 2D NMR data handling and preparation (the Global Peak List and Vectorization approaches) and to compare them (with respect to each other and with 1D standards). This will allow to detect which methodology is the best in terms of amount of metabolomic content and to explore the advantages of the selected workflow in distinguishing among treatment groups and identifying relevant biomarkers. Therefore, this paper explores both the necessity of novel 2D pre-processing workflows, the evaluation of their quality and the evaluation of their performance in the subsequent determination of accurate (2D) biomarkers. Methods To select the more informative data source, MIC (Metabolomic Informative Content) indexes are used, based on clustering and inertia measures of quality. Then, to highlight biomarkers or critical spectral zones, the PLS-DA model is used, along with more advanced sparse algorithms (sPLS and L-sOPLS). Results Results are discussed according to two different experimental designs (one which is unsupervised and based on human urine samples, and the other which is controlled and based on spiked serum media). MIC indexes are shown, leading to the choice of the more relevant workflow to use thereafter. Finally, biomarkers are provided for each case and the predictive power of each candidate model is assessed with cross-validated measures of RMSEP. Conclusion In conclusion, it is shown that no solution can be universally the best in every case, but that 2D experiments allow to clearly find relevant cross peak biomarkers even with a poor initial separability between groups. The MIC measures linked with the candidate workflows (2D GPL, 2D vectorization, 1D, and with specific parameters) lead to visualize which data set must be used as a priority to more easily find biomarkers. The diversity of data sources, mainly 1D versus 2D, may often lead to complementary or confirmatory results. [less ▲]

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See detailMetabolomics for the discovery of new therapeutic approach and personalized medicine: the case of exudative Age-related Macular Degeneration.
LAMBERT, Vincent ULiege; Schoumacher, Matthieu ULiege; Lecomte, Julie ULiege et al

Conference (2018, September 19)

. Introduction Age-related Macular Degeneration (AMD) is the leading cause of blindness among the elderly population in developed countries. 90% of all vision loss due to AMD result from the exudative ... [more ▼]

. Introduction Age-related Macular Degeneration (AMD) is the leading cause of blindness among the elderly population in developed countries. 90% of all vision loss due to AMD result from the exudative form, which is characterized by choroidal neovascularization (CNV)1. Treatment is mainly based on regular intra-vitreal injection of anti-VEGF to stabilize CNV. Nevertheless, the comprehensive understanding of the pathogenesis and the evolution of this complex multi-factorial disease remain incomplete. Moreover, due to the long-term disease chronicity and to some resistance to treatment, a continuous follow-up of patients, a personalization of treatment and the discovery of new therapeutic approaches are mandatory. 2. Approach Metabolomics provides a unique and direct vision of the functional outcome of organism’s activities that could be correlated to pathologies and/or treatment administration. The links between metabolic changes, patient phenotypes, physiological and/or pathological status and treatment are now well established and have opened a new area for the application of metabolomics in target identification and in personalized medicine2. In order to study CNV occurrence and evolution and to get novel and innovative insights into AMD, we decided to apply a NMR-based metabolomics approach on both clinical and pre-clinical models (a murine laser-induced CNV model and patient’s cohorts). Sera samples coming from 97 healthy volunteers and 95 exudative AMD patients have been collected during ophthalmic exams at the CHU of Liège. Patients were separated into bleeder AMD group (patients with AMD in bleeding phase) and non-bleeder AMD group (patients with non-bleeding AMD). The CNV mice model mimics the exudative phase of AMD and allows the dynamic study of CNV evolution. 3. Results Metabolomics approach applied to the human cohorts led to a separation between healthy and non-healthy patients as well as between bleeder and non-bleeder groups. Few metabolites are linked to this discrimination. Among those, lactate and lipoproteins profile emerge as the main key metabolites. Higher lactate level was detected in patients during bleeding phase while low-density lipoproteins (LDL) and very low density lipoproteins (VLDL) levels seems to be increased in AMD patients. In the mice model, metabolomics profiles varied according to CNV occurrence. In this case again, lactate and lipoproteins profile were related to this evolution. Pharmacological normalization of lactate levels by blocking pyruvate deshydrogenase kinase (PDK) or by modulating LDH activity in the mice model, inhibits CNV formation, Moreover, CNV inhibition by anti-angiogenic drugs led also to a reduction of systemic lactate level. 4. Discussion Mechanistically, we have demonstrated through a combination of NMR measurements (both 1D and 2D), pharmacological modulation and molecular biology approaches, that lactate, initially produced in the eyes then at the systemic level, plays a critical role in the onset of the inflammatory and angiogenic phases. Targeting lactate level by a modulation of PDK appears to be an alternative to intra-vitreal injection of anti-VEGF and a putative new therapeutic approach to reduce CNV progression. Moreover, changes in lipoproteins profile could also be correlated with AMD and CNV progression and then could be a nice marker of the progression of the pathology. A longitudinal patients follow-up during anti-VEGF treatment is currently running while MS-based targeted metabolomics and lipidomics studies are planned to validate and deepen our first findings. Altogether, we demonstrated that metabolomics is a suitable tool to deep insight into pathologies and to identify some metabolites as functional, traceable and targetable molecules that open new perspectives for optimizing and personalizing treatment and patient follow-up. References 1. Ambati, J., & Fowler, B. (2012). Mechanisms of age-related macular degeneration. Neuron, 75(1), 26–39. http://doi.org/10.1016/j.neuron.2012.06.018 2. Jacob, M., Lopata, A. L., Dasouki, M., & Abdel Rahman, A. M. (2017). Metabolomics toward personalized medicine. Mass Spectrometry Reviews, (September). http://doi.org/10.1002/mas.21548 [less ▲]

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See detailPepsNMR for 1H NMR metabolomic data pre-processing
Martin, Manon; Legat, Benoît; Leenders, Justine ULiege et al

in Analytica Chimica Acta (2018), 1019

In the analysis of biological samples, control over experimental design and data acquisition procedures alone cannot ensure well-conditioned 1H NMR spectra with maximal information recovery for data ... [more ▼]

In the analysis of biological samples, control over experimental design and data acquisition procedures alone cannot ensure well-conditioned 1H NMR spectra with maximal information recovery for data analysis. A third major element affects the accuracy and robustness of results: the data pre-processing/pre-treatment for which not enough attention is usually devoted, in particular in metabolomic studies. The usual approach is to use proprietary software provided by the analytical instruments' manufacturers to conduct the entire pre-processing strategy. This widespread practice has a number of advantages such as a user-friendly interface with graphical facilities, but it involves non-negligible drawbacks: a lack of methodological information and automation, a dependency of subjective human choices, only standard processing possibilities and an absence of objective quality criteria to evaluate pre-processing quality. This paper introduces PepsNMR to meet these needs, an R package dedicated to the whole processing chain prior to multivariate data analysis, including, among other tools, solvent signal suppression, internal calibration, phase, baseline and misalignment corrections, bucketing and normalisation. Methodological aspects are discussed and the package is compared to the gold standard procedure with two metabolomic case studies. The use of PepsNMR on these data shows better information recovery and predictive power based on objective and quantitative quality criteria. Other key assets of the package are workflow processing speed, reproducibility, reporting and flexibility, graphical outputs and documented routines [less ▲]

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See detailNMR-based Metabolomics for New Target Discovery and Personalized Medicine: Application to Age-Related Macular Degeneration (AMD).
Schoumacher, Matthieu ULiege; LAMBERT, Vincent ULiege; Leenders, Justine ULiege et al

Conference (2018, July 05)

Abstract: Nuclear Magnetic Resonance (NMR) is an indispensable analytical tool for research in the biomedical and pharmaceutical fields. More recently, NMR appeared as one of the major and more powerful ... [more ▼]

Abstract: Nuclear Magnetic Resonance (NMR) is an indispensable analytical tool for research in the biomedical and pharmaceutical fields. More recently, NMR appeared as one of the major and more powerful technological platform for metabolomics approach. Metabolomics is a growing area of the “omics” sciences and is defined as the comprehensive identification and quantification of lowmolecular weight metabolites in biological samples. It provides a unique and direct vision of the functional outcome of organism’s activities that could be correlated to pathologies and/or treatment administration. The links between metabolic changes, patient phenotype, physiological and/or pathological status and treatment are now well established and have opened a new area for the application of metabolomics in new target identification and in personalized medicine. Age-related Macular Degeneration (AMD) is the leading causes of blindness among the elderly population in developed countries. 90% of all vision loss due to AMD result from the exudative form, which is characterized by choroidal neovascularization (CNV). Treatment is mainly based on regular intravitreal injection of anti-VEGF to stabilize CNV. Nevertheless, the comprehensive understanding of the pathogenesis and the evolution of this complex multi-factorial disease remain incomplete. Moreover, due to the long-term disease chronicity and to some resistance to treatment, a continuous follow-up of patients, a personalization of treatment and the discovery of new therapeutic approaches are mandatory. In order to study CNV occurrence and evolution and to get new and innovative insights into this pathology, we decided to apply a NMR-based metabolomics approach on both clinical and pre-clinical models (a murine laser-induced CNV model and patient’s cohorts). This approach led us to identify some metabolites linked to CNV developments in both human and murine samples. These molecules could be considered not only as markers of the pathology but also as putative target for a new treatment of AMD. Among those, lactate emerges as a key metabolite in both settings. Mechanistically, we demonstrated that lactate, initially produced in the eyes increases at the systemic level and play a critical role in the onset of the inflammatory and angiogenic phases. For this purpose, we use a combination of NMR measurements (both 1D and 2D) and molecular biology approaches. The control of the systemic concentration of lactate by PDHK inhibition or by LDH modulation decreases significantly CNV development. Based on a metabolomics approach, our data support the innovative concept of lactate as a putative target for a new therapeutic approach of AMD as well as a useful marker for patient’s follow-up during treatment. We highlight also the utility and the efficacy of NMR for metabolomics and metabolites measurement in complex biological samples. [less ▲]

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See detailNMR-based metabolomics for new target discovery and personalized medicine : application to Age-related Macular Degeneration (AMD).
De Tullio, Pascal ULiege

Conference (2018, July 01)

Nuclear Magnetic Resonance (NMR) is an indispensable analytical tool for research in the biomedical and pharmaceutical fields. More recently, NMR appeared as one of the major and more powerful ... [more ▼]

Nuclear Magnetic Resonance (NMR) is an indispensable analytical tool for research in the biomedical and pharmaceutical fields. More recently, NMR appeared as one of the major and more powerful technological platform for metabolomics approach. Metabolomics is a growing area of the “omics” sciences and is defined as the comprehensive identification and quantification of low-molecular weight metabolites in biological samples. It provides a unique and direct vision of the functional outcome of organism’s activities that could be correlated to pathologies and/or treatment administration. The links between metabolic changes, patient phenotype, physiological and/or pathological status and treatment are now well established and have opened a new area for the application of metabolomics in new target identification and in personalized medicine. Age-related Macular Degeneration (AMD) is the leading causes of blindness among the elderly population in developed countries. 90% of all vision loss due to AMD result from the exudative form, which is characterized by choroidal neovascularization (CNV). Treatment is mainly based on regular intravitreal injection of anti-VEGF to stabilize CNV. Nevertheless, the comprehensive understanding of the pathogenesis and the evolution of this complex multi-factorial disease remain incomplete. Moreover, due to the long-term disease chronicity and to some resistance to treatment, a continuous follow-up of patients, a personalization of treatment and the discovery of new therapeutic approaches are mandatory. In order to study CNV occurrence and evolution and to get new and innovative insights into this pathology, we decided to apply a NMR-based metabolomics approach on both clinical and pre-clinical models (a murine laser-induced CNV model and patient’s cohorts). This approach led us to identify some metabolites linked to CNV developments in both human and murine samples. These molecules could be considered not only as markers of the pathology but also as putative target for a new treatment of AMD. Among those, lactate emerges as a key metabolite in both settings. Mechanistically, we demonstrated that lactate, initially produced in the eyes increases at the systemic level and play a critical role in the onset of the inflammatory and angiogenic phases. For this purpose, we use a combination of NMR measurements (both 1D and 2D) and molecular biology approaches. The control of the systemic concentration of lactate by PDHK inhibition or by LDH modulation decreases significantly CNV development. Based on a metabolomics approach, our data support the innovative concept of lactate as a putative target for a new therapeutic approach of AMD as well as a useful marker for patient’s follow-up during treatment. We highlight also the utility and the efficacy of NMR for metabolomics and metabolites measurement in complex biological samples. [less ▲]

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See detailCodon-specific translation reprogramming promotes resistance to targeted therapy
Rapino, Francesca ULiege; Delaunay, Sylvain ULiege; Rambow, Florian et al

in Nature (2018), 558

Reprogramming of mRNA translation has a key role in cancer development and drug resistance. However, the molecular mechanisms that are involved in this process remain poorly understood. Wobble tRNA ... [more ▼]

Reprogramming of mRNA translation has a key role in cancer development and drug resistance. However, the molecular mechanisms that are involved in this process remain poorly understood. Wobble tRNA modifications are required for specific codon decoding during translation. Here we show, in humans, that the enzymes that catalyse modifications of wobble uridine 34 (U34) tRNA (U34 enzymes) are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAFV600E oncogene and by resistance to targeted therapy in melanoma. We show that BRAFV600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signalling and ELP3 or CTU1 and/or CTU2 synergizes to kill melanoma cells. Activation of the PI3K signalling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A mRNA and the maintenance of high levels of HIF1α protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1α. Together, these results demonstrate that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation. [less ▲]

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See detailEndometriosis: a deep insight into the pathology through metabolomics
Leenders, Justine ULiege; Martin, Manon; NISOLLE, Michelle ULiege et al

Poster (2018, June)

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See detailGUT MICROBIOTA AND FAECAL LEVELS OF SHORT CHAIN FATTY ACIDS DIFFER UPON BLOOD PRESSURE LEVELS IN MAN
HUART, Justine ULiege; Leenders, Justine ULiege; Taminiau, Bernard ULiege et al

in Nephrology Dialysis Transplantation (2018, May 18), 33(Issue suppl_1), 368369

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See detailEndometriosis: deep insight into the pathology through metabolomics
Leenders, Justine ULiege; Martin, Manon; NISOLLE, Michelle ULiege et al

Poster (2018, May)

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See detailNOTA‐PRGD2 and NODAGA‐PRGD2: Bioconjugation, characterization, radiolabelling, and design space
Salvé, Mallory ULiege; Avohou, Tonakpon Hermane ULiege; Monbaliu, Jean-Christophe ULiege et al

in Journal of Labelled Compounds and Radiopharmaceuticals (2018), 61

This work reports on the development of amide bond bioconjugation for the production of ‐NOTA and ‐NODAGA PRGD2 using batch strategy andmicrofluidic reactor technology. The final radiolabelling step was ... [more ▼]

This work reports on the development of amide bond bioconjugation for the production of ‐NOTA and ‐NODAGA PRGD2 using batch strategy andmicrofluidic reactor technology. The final radiolabelling step was fully optimized using Design of Experiments and Design Space approaches, hence targeting robust labelling yields in routine. Optimal labelling conditions were defined insodium acetate buffer as 168 μg/mL peptide concentration, 4.9 pH, 47.5°C temperature, and 12.5‐minute reaction time. Upon optimization, the Gallium‐68 radiolabelling was fully automated. All the work was designed to be compliant to the GMP environment and to support the pharmaceuticalscale‐up. [less ▲]

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See detailA NMR-based metabolomics approach for reducing food losses: the example of minced pork meat
Cauchie, Emilie ULiege; Korsak Koulagenko, Nicolas ULiege; Leenders, Justine ULiege et al

in Proceedings of the First international Conference on "Innovative Food Ingredients and Food safety" (2018)

In Europe, the losses of initial meat production represent 20% and more than half of this occurs at animal production, slaughtering, processing and distribution step. In order to control food waste ... [more ▼]

In Europe, the losses of initial meat production represent 20% and more than half of this occurs at animal production, slaughtering, processing and distribution step. In order to control food waste, studies have highlighted the importance of monitoring the microbial diversity of food products because spoilage by bacteria that contaminate the food matrix is a major issue. As such, the combination of metabolomics data with other complementary approaches (classical microbiology and quality parameters) can gives the opportunity to gain deeper insights into and have a better comprehension of the spoilage mechanisms. The aim of the current study was to assess meat spoilage through the evolution of bacterial counts and changes in the metabolic profile of minced pork meat using Nuclear Magnetic Resonance (NMR) based metabolomics. Microbiological assessment, pH measurements, gas composition and metabolomics analysis were carried out in meat samples stored under food wrap and under modified atmosphere packaging (70% O2 – 30% CO2) at 4, 8 and 12°C during 13 days. All samples were irradiated and then inoculated separately with three dominant bacterial species: Brochothrix thermosphacta, Leuconostoc gelidum and Pseudomonas fragi. For all conditions, non-inoculated samples were also stored. Analysis were carried out at day 0 and at day 13 for metabolomics analysis, and each day for all others measurements. The multivariate analysis (PLS-DA) reveals a clear discrimination between: (i) the non-inoculated product at day 0 and at day 13, (ii) the inoculated and non-inoculated samples, (iii) the type of bacterium, and (iv) the packaging conditions. It can be observed that the type of bacterium inoculated had a higher impact on the metabolome than that the packaging conditions. Moreover, some metabolites are significantly increased: acetate and glycerol for B. thermosphacta, betaine and lactate for L. gelidum, threonine and glycine for P. fragi. Exploration of the correlations of NMR-based metabolomics results with others microbial parameters suggested their use as possible spoilage tool to provide information on minced pork meat spoilage and to follow intrinsically the evolution of the metabolomics pattern linked to a specific bacterium in a complex bacterial ecosystem. [less ▲]

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See detailCXCL12 and MYC control energy metabolism to support adaptive responses after kidney injury.
Yakulov, Toma A.; Todkar, Abhijeet P.; Slanchev, Krasimir et al

in Nature Communications (2018), 9(1), 3660

Kidney injury is a common complication of severe disease. Here, we report that injuries of the zebrafish embryonal kidney are rapidly repaired by a migratory response in 2-, but not in 1-day-old embryos ... [more ▼]

Kidney injury is a common complication of severe disease. Here, we report that injuries of the zebrafish embryonal kidney are rapidly repaired by a migratory response in 2-, but not in 1-day-old embryos. Gene expression profiles between these two developmental stages identify cxcl12a and myca as candidates involved in the repair process. Zebrafish embryos with cxcl12a, cxcr4b, or myca deficiency display repair abnormalities, confirming their role in response to injury. In mice with a kidney-specific knockout, Cxcl12 and Myc gene deletions suppress mitochondrial metabolism and glycolysis, and delay the recovery after ischemia/reperfusion injury. Probing these observations in zebrafish reveal that inhibition of glycolysis slows fast migrating cells and delays the repair after injury, but does not affect the slow cell movements during kidney development. Our findings demonstrate that Cxcl12 and Myc facilitate glycolysis to promote fast migratory responses during development and repair, and potentially also during tumor invasion and metastasis. [less ▲]

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See detailRadiotherapy-activated cancer-associated fibroblasts promote tumor progression through paracrine IGF-1R activation.
Tommelein, Joke; De Vlieghere, Elly; Verset, Laurine et al

in Cancer Research (2018)

Preoperative radiotherapy (RT) is a mainstay in the management of rectal cancer (RC), a tumor characterized by desmoplastic stroma containing cancer-associated fibroblasts (CAF). Although CAF are ... [more ▼]

Preoperative radiotherapy (RT) is a mainstay in the management of rectal cancer (RC), a tumor characterized by desmoplastic stroma containing cancer-associated fibroblasts (CAF). Although CAF are abundantly present, the effects of RT to CAF and its impact on cancer cells are unknown. We evaluated the damage responses of CAF to RT and investigated changes in colorectal cancer (CRC) cell growth, transcriptome, metabolome, and kinome in response to paracrine signals emerging from irradiated CAF. RT to CAF induced DNA damage, p53 activation, cell cycle arrest, and secretion of paracrine mediators including insulin-like growth factor-1 (IGF-1). Subsequently, RT-activated CAF promoted survival of CRC cells as well as a metabolic switch favoring glutamine consumption through IGF-1 receptor (IGF-1R) activation. RT followed by IGF-1R neutralization in orthotopic CRC models reduced the number of mice with organ metastases. Activation of the downstream IGF-1R mediator mTOR was significantly higher in matched (intrapatient) samples and in unmatched (interpatient) samples from RC patients after neoadjuvant chemoRT. Taken together, our data support the notion that paracrine IGF-1/IGF-1R signaling initiated by RT-activated CAF worsen CRC progression, establishing a preclinical rationale to target this activation loop to further improve clinical responses and patient survival. [less ▲]

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