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See detailKidney-targeted radiotherapy triggers renal ischaemic preconditioning in mice
Khbouz, Badr ULiege; LALLEMAND, François ULiege; ROWART, Pascal ULiege et al

Conference (2021, November 26)

INTRODUCTION | Renal ischemia/reperfusion (I/R) is the leading cause of acute kidney injury (AKI). Ischemic preconditioning (IPC) may help to attenuate the severity of I/Rassociated AKI. Whole-body ... [more ▼]

INTRODUCTION | Renal ischemia/reperfusion (I/R) is the leading cause of acute kidney injury (AKI). Ischemic preconditioning (IPC) may help to attenuate the severity of I/Rassociated AKI. Whole-body irradiation induces renal IPC in mice, although the pathways remain largely unknown. Furthermore, the impact of kidney-centred irradiation on renal resistance against I/R has not been studied. First, we comprehensively investigate the pathways involved in renal irradiation. Next, we assess the functional impact of renal irradiation applied I/R injury. Finally, we test whether Sunitinib-mediated inhibition of the angiogenesis prevents irradiation-associated IPC. METHODS | Exp1: Renal irradiation (8.5Gy) was performed in male C57bl/6 mice(n=10). One month later, total kidney RNA was extracted from irradiated and control (n=5) mice for comparative RNA-Seq. Exp2: After renal irradiation, the right kidneys were removed, and the left kidneys undergo ischemia(30min)/reperfusion(48h) at Days 7-14-28 post irradiation(n=8). Exp3: Following the same protocol of I/R at Day14, 3 groups were compared(n=8): 1/irradiation; 2/irradiation and gavage with Sunitinib from Day2 to 13; 3/control group without irradiation or gavage. RESULTS | Exp1: RNAseq showen up-regulation of angiogenesis signalling pathways. Expressions of angiogenesis markers (CD31, VEGF) showed an increase at both mRNA and protein levels in irradiated kidneys (p<0.01). Exp2: Following I/R, Blood Urea Nitrogen (BUN) and Creatinine (SCr) levels were lower in the irradiated mice compared to controls: (BUN: 86.2±6.8 vs. 454.5±27.2mg/dl; SCr: 0.1±0.01 vs. 1.7±0.2mg/dl, p<0.01). The renal infiltration by CD11b-(187±32 vs 477±20/mm2) and F4-80-positive cells (110±22 vs 212±25/mm2) was reduced in the irradiated group. VEGF and CD31 expression was increased in irradiated kidneys at both mRNA and protein levels(p<0,01). Exp3: One-way analysis of variance followed by Tukey’s test showed that, following I/R, BUN and SCr levels were lower in the irradiated group compared to controls (BUN: 106.1±33.6 vs. 352.2±54.3mg/dl; SCr: 0.3±0.13 vs. 1±0.2mg/dl), and in irradiated group compared to the irradiated-exposed group to Sunitinib (BUN: 106.1±33.6 vs. 408.4±54.9mg/dl; SCr: 0.3±0.12 vs. 1.5±0.3mg/dl; p<0.01). CONCLUSION | Renal irradiation induces the activation of angiogenesis in mice. Renal irradiation leads to IPC, with preserved renal function and attenuated inflammation post I/R. Exposure to the anti-angiogenic drug Sunitinib post-irradiation prevents the irradiation-induced IPC. [less ▲]

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See detailLe médicament anti-angiogénique Sunitinib contrarie le conditionnement ischémique rénal induit par l’irradiation
Khbouz, Badr ULiege; LALLEMAND, François ULiege; Pasal, Rowart ULiege et al

Conference (2021, October 06)

Introduction L’irradiation corporelle induit un conditionnement ischémique rénal(CIR) chez la souris. Les mécanismes cellulaires sont méconnus, hormis un possible rôle de la néo-angiogenèse. Description ... [more ▼]

Introduction L’irradiation corporelle induit un conditionnement ischémique rénal(CIR) chez la souris. Les mécanismes cellulaires sont méconnus, hormis un possible rôle de la néo-angiogenèse. Description claire et complète de l'expérience Dans cette étude, nous étudions les voies impliquées dans l'irradiation rénale. Ensuite, nous analysons l'impact fonctionnel sur les reins avant ischémie rénale/reperfusion(I/R). Enfin, nous testons si l'inhibition de l'angiogenèse par le Sunitinib empêche le CIR associé à l'irradiation. Méthodes (une explication détaillée de votre analyse est attendue) Exp1. Une irradiation rénale(8Gy) est réalisée chez des C57bl/6 mâles(n=10). Un mois plus tard, l'ARN rénal total est extrait pour un RNAseq comparatif. Exp2. À 7- 14-28 jours post irradiation rénale, les reins droits sont néphrectomisés et les reins gauches subissent une ischémie(30min)/reperfusion(48h) (n=8/timing). Exp3. Suivant le même protocole d'I/R à J14, 3 groupes sont comparés(n=8/groupe) : 1/ irradiation ; 2 /irradiation et gavage au Sunitinib de J2 à J13 ; 3/ groupe témoin sans irradiation ni gavage. Résultats obtenus ou attendus Exp1. RNAseq montre une up-régulation des voies de l'angiogenèse. L’expression de VEGF et CD31 est significativement augmentée au niveau ARNm et protéique dans les reins irradiés. Exp2. Après I/R à J14 post irradiation, les taux sériques d’urée(BUN) et de créatinine(SCr) sont plus faibles chez les souris irradiées par rapport aux témoins(BUN : 86,2±6,8 vs 454,5±27,2 mg/dl ; SCr: 0,1±0,01 vs 1,7±0,2 mg/dl, p<0,01). L'infiltration rénale par les macrophages CD11b(187±32 vs 477±20/mm²) et F4-80(110±22 vs 212±25/mm²) est significativement moindre dans le groupe irradié. L'expression de VEGF et CD31 est majorée dans les reins irradiés à partir de J14. Exp3. Après I/R, les taux sériques de BUN et de SCr dans le groupe irradié-exposé au Sunitinib sont similaires au groupe contrôle(BUN 352,2±54,3 vs. 408,4 ± 54,9 mg/dl ; SCr : 1,5±0,3 vs. 1±0,2 mg/dl). Conclusion L'irradiation rénale induit l'activation de l'angiogenèse chez la souris et est associée à un CIR, avec fonction rénale préservée et inflammation atténuée post I/R. L'exposition au Sunitinib post-irradiation empêche ce CIR. [less ▲]

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See detailThe irradiation-induced renal ischemic preconditioning is blunted by the oral administration of the anti-angiogenic agent, Sunitinib
Khbouz, Badr ULiege; LALLEMAND, François ULiege; Rowart, Pascal ULiege et al

Conference (2021, August 30)

Background: Whole-body irradiation induces renal ischemic preconditioning (RIP) in mice, possibly via neoangiogenesis. Here, we test whether Sunitinib-mediated inhibition of angiogenesis prevents the ... [more ▼]

Background: Whole-body irradiation induces renal ischemic preconditioning (RIP) in mice, possibly via neoangiogenesis. Here, we test whether Sunitinib-mediated inhibition of angiogenesis prevents the irradiation-associated RIP. ● Methods: After kidney-centred irradiation (8.56 Gy), the right kidneys were removed and harvested, and the left kidneys underwent ischemia (30min) / reperfusion (48h) (I/R) at Day 14. Three groups were compared (n=8/group): 1/irradiation; 2/irradiation and gavage with Sunitinib (40 mg/kg) from D2 to D13; 3/control group without irradiation or gavage. Renal sections from the 3 groups post-I/R were stained by Periodic Acid Schiff (PAS). I/R-associated acute tubular necrosis was blindly evaluated by a renal pathologist using the histological Jablonski score. The expression of inflammatory markers CD11b and F4/80 was comparatively quantified by immunostaining. The expression of vascular markers CD31 and VEGF in nonischemic kidneys were quantified by real-time qPCR. ● Results: One-way analysis of variance followed by Tukey’s test showed that, following I/R, serum levels of urea (BUN) and creatinine (SCr) were significantly lower in pre-irradiated mice compared to controls (BUN: 106.1±33.6 vs. 352.2±54.3mg/dl; SCr: 0.3±0.13 vs. 1±0.2mg/dl), as well as in pre-irradiated mice compared to the irradiated mice fed with Sunitinib (BUN: 106.1±33.6 vs. 408.4±54.9mg/dl; SCr: 0.3±0.12 vs. 1.5±0.3mg/dl). No difference was observed between the Sunitinib group and the control group. Jablonski’s severity score was lower in pre-irradiated mice compared to control group and Sunitinib group (p<0.01). The renal infiltration by CD11b- (560±32 vs. 308±21/mm²) and F4-80 positive cells (430±35 vs. 312±19/mm²) was significantly reduced in the irradiated group compared to controls. At mRNA levels, the renal expression of VEGF and CD31 was increased in the irradiated group but not in the Sunitinib group (p<0.01). ● Conclusions: Renal irradiation before I/R is associated with preserved renal function and attenuated inflammation post I/R. Sunitinib administration prevents the irradiation-induced RIP. [less ▲]

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See detailEffect of renal irradiation in neo-angiogenesis and ischemic preconditioning
Khbouz, Badr ULiege; LALLEMAND, François ULiege; Rowart, Pascal ULiege et al

Conference (2021, June 05)

Background and Aims: Whole-body irradiation has been suggested to induce renal ischemic preconditioning (RIP) in rodent models, possibly via neo-angiogenesis. First, we comprehensively investigate the ... [more ▼]

Background and Aims: Whole-body irradiation has been suggested to induce renal ischemic preconditioning (RIP) in rodent models, possibly via neo-angiogenesis. First, we comprehensively investigate the pathways involved in kidney-centered irradiation. Next, we assess the functional and structural impact of kidney-centered irradiation applied before ischemia/reperfusion (I/R) injury. Finally, we test whether Sunitinib-mediated inhibition of the neo-angiogenesis prevents irradiation-associated RIP. Method: Experiment 1: Unilateral irradiation of the left kidney (8.56 Gy) was performed in male 10-week-old wild-type C57bl/6 mice (n=10). One month later, total kidney RNAs were extracted from irradiated and control (n=5) mice for comparative high-throughput RNA-Seq (using BaseSpace Sequence Hub Illumina). Functional enrichment analysis was performed using Database for Annotation, Visualization and Integrated Discovery (DAVID). Experiment 2: Two x-ray beams (225Kv, 13mA) specifically targeted both kidneys for a total dose of 8.56Gy. Fourteen days later, the right kidneys were removed and harvested, and the left kidneys undergo 30-minute ischemia followed by 48-hour reperfusion (n=8). Experiment 3: Following the same protocol of renal I/R, 3 groups of male 10-week-old wild-type C57bl/6 mice were compared (n=8 animals per group): 1/ irradiation 2/ irradiation and gavage with Sunitinib for 14days 3/ control group without irradiation or gavage. All groups undergo an I/R after treatments. Results: Experiment 1: Comparative transcriptomics showed a significant up-regulation of various signaling pathways, including angiogenesis (HMOX1) and stress response (HSPA1A, HSPA1B). Expressions of angiogenesis markers (CD31, TGFb1, HMOX1) shows an increase at both mRNA (real-time qPCR) and protein (immune-staining) levels in irradiated kidneys compared to controls (p<0.01). Experiment 2: Following I/R, the blood urea nitrogen (BUN) and serum creatinine (SCr) levels were significantly lower in the irradiated animals compared to controls: (BUN: 86.2±6.8 vs. 454.5±27.2mg/dl; SCr: 0.1±0.01 vs. 1.7±0.2mg/dl, p<0.01). The renal infiltration by CD11b-positive cells (187±32 vs. 477±20/mm²) and F4-80 macrophages (110±22 vs. 212±25/mm²) was significantly reduced in the irradiated group. The real-time qPCR mRNA levels of the angiogenic markers, TGFb1 and CD31, were significantly increased in the irradiated group compared to controls (p<0,01). The CD31-immunostaining was increased in irradiated group compared to controls (p<0.01). Experiment 3: Following I/R, the serum levels of BUN and SCr were lower in pre-irradiated animals compared to controls (BUN: 106.1±33.6 vs. 352.2±54.3mg/dl; SCr: 0.3±0.13 vs. 1±0.2mg/dl), and to the irradiated-exposed group to Sunitinib (BUN: 106.1±33.6 vs. 408.4±54.9mg/dl; SCr: 0.3±0.12 vs. 1.5±0.3mg/dl; p<0.01). No difference observed between the irradiated-exposed mice to Sunitnib and the controls. Conclusion: Renal irradiation induces the activation of signaling pathways involved in angiogenesis in mice. Renal irradiation causes ischemic preconditioning, with preserved renal function and attenuated inflammation post I/R. Exposure to the anti-angiogenic drug Sunitinib post-irradiation prevents the irradiation-induced nephroprotection against I/R. [less ▲]

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See detailThe irradiation-induced renal ischemic preconditioning is blunted by the oral administration of the anti-angiogenic agent, Sunitinib
Khbouz, Badr ULiege; LALLEMAND, François ULiege; Rowart, Pascal ULiege et al

Poster (2021, May 27)

● Objective: Irradiation has been suggested to induce renal ischemic preconditioning (RIP) in mice, possibly via angiogenesis. First, we comprehensively investigate the pathways involved in kidneys ... [more ▼]

● Objective: Irradiation has been suggested to induce renal ischemic preconditioning (RIP) in mice, possibly via angiogenesis. First, we comprehensively investigate the pathways involved in kidneys-centered irradiation. Next, we assess the functional impact of renal irradiation applied before renal ischemia/reperfusion (I/R) injury. Finally, we test whether Sunitinib-mediated inhibition of the angiogenesis prevents irradiation-associated RIP. ● Methods: Exp1: Renal irradiation (8.56 Gy) was performed in male C57bl/6 mice (n=10). One month later, total kidney RNA was extracted from irradiated and control (n=5) mice for comparative RNA-Seq. Exp2: After renal irradiation, the right kidneys were removed, and the left kidneys undergo ischemia(30min)/reperfusion(48h) at Days 7-14-28 post irradiation (n=8). Exp3: Following the same protocol of I/R at Day14, 3 groups were compared (n=8): 1/irradiation; 2/irradiation and gavage with Sunitinib from Day2 to 13; 3/control group without irradiation or gavage. ● Results: Exp1: RNA-Seq showed up-regulation of angiogenesis signaling pathways. Expressions of angiogenesis markers (CD31, VEGF) showed an increase at both mRNA and protein levels in irradiated kidneys (p<0.01). Exp2: Following I/R, BUN and SCr levels were lower in the irradiated mice compared to controls: (BUN: 86.2±6.8 vs. 454.5±27.2mg/dl; SCr: 0.1±0.01 vs. 1.7±0.2mg/dl, p<0.01). The renal infiltration by CD11b (187±32 vs. 477±20/mm²) and F4-80 positive cells (110±22 vs.212±25/mm²) was reduced in the irradiated group. VEGF and CD31, were increased in irradiated kidneys at both mRNA and protein levels (p<0,01). Exp3: One-way analysis of variance followed by Tukey’s test showed that, following I/R, BUN and SCr levels were lower in irradiated group compared to controls (BUN: 106.1±33.6 vs. 352.2±54.3mg/dl; SCr: 0.3±0.13 vs. 1±0.2mg/dl), and in irradiated group compared to the irradiated-exposed group to Sunitinib (BUN: 106.1±33.6 vs. 408.4±54.9mg/dl; SCr: 0.3±0.12 vs. 1.5±0.3mg/dl; p<0.01). ● Conclusions: Kidneys-centered irradiation induces the activation of angiogenesis pathways in mice. Renal irradiation leads to RIP, with preserved renal function and attenuated inflammation post I/R. Exposure to the anti-angiogenic drug Sunitinib post-irradiation prevents the irradiation-induced RIP. [less ▲]

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See detailTumor resistance to ferroptosis driven by Stearoyl-CoA Desaturase-1 (SCD1) in cancer cells and Fatty Acid Biding Protein-4 (FABP4) in tumor microenvironment promote tumor recurrence.
Luis, Géraldine ULiege; Godfroid, Adrien ULiege; Nishiumi, Shin et al

in Redox Biology (2021), 43

PROBLEM: Tumor recurrence is a major clinical issue that represents the principal cause of cancer-related deaths, with few targetable common pathways. Mechanisms by which residual tumors persist and ... [more ▼]

PROBLEM: Tumor recurrence is a major clinical issue that represents the principal cause of cancer-related deaths, with few targetable common pathways. Mechanisms by which residual tumors persist and progress under a continuous shift between hypoxia-reoxygenation after neoadjuvent-therapy are unknown. In this study, we investigated the role of lipid metabolism and tumor redox balance in tumor recurrence. METHODS: Lipidomics, proteomics and mass spectrometry imaging approaches where applied to mouse tumor models of recurrence. Genetic and pharmacological inhibitions of lipid mediators in tumors were used in vivo and in functional assays in vitro. RESULTS: We found that stearoyl-CoA desaturase-1 (SCD1) expressed by cancer cells and fatty acid binding protein-4 (FABP4) produced by tumor endothelial cells (TECs) and adipocytes in the tumor microenvironment (TME) are essential for tumor relapse in response to tyrosine kinase inhibitors (TKI) and chemotherapy. SCD1 and FABP4 were also found upregulated in recurrent human breast cancer samples and correlated with worse prognosis of cancer patients with different types of tumors. Mechanistically, SCD1 leads to fatty acid (FA) desaturation and FABP4 derived from TEM enhances lipid droplet (LD) in cancer cells, which cooperatively protect from oxidative stress-induced ferroptosis. We revealed that lipid mobilization and desaturation elicit tumor intrinsic antioxidant and anti-ferroptotic resources for survival and regrowth in a harsh TME. Inhibition of lipid transport from TME by FABP4 inhibitor reduced tumor regrowth and by genetic - or by pharmacological - targeting SCD1 in vivo, tumor regrowth was abolished completely. CONCLUSION: This finding unveils that it is worth taking advantage of tumor lipid addiction, as a tumor vulnerability to design novel treatment strategy to prevent cancer recurrence. [less ▲]

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See detailEstetrol combined to progestogen for menopause or contraception indication is neutral on breast cancer
Gallez, Anne ULiege; Blacher, Silvia ULiege; Maquoi, Erik ULiege et al

in Cancers (2021)

Hormonal treatments, especially those used to treat menopause symptoms are known to increase breast cancer risk. It is thus necessary to identify new formulations with a better benefit/risk pro-file. The ... [more ▼]

Hormonal treatments, especially those used to treat menopause symptoms are known to increase breast cancer risk. It is thus necessary to identify new formulations with a better benefit/risk pro-file. The aim of this translational study was to evaluate the breast cancer risk associated to a combination of a natural estrogen, named estetrol, with progestogens such as natural progesterone and drospirenone. Since the assessment of breast cancer risk in patients during drug development is not possible given the requirement of long-term studies in large populations, this study provides new evidences that a therapeutic dose of estetrol for menopause treatment or contraception, combined with progesterone or drospirenone, may provide a better benefit/risk profile towards breast cancer risk compared to hormonal treatments currently available for patients. [less ▲]

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See detailTyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy.
POTTIER, Charles ULiege; Fresnais, Margaux; Gilon, Marie ULiege et al

in Cancers (2020)

Receptor tyrosine kinases (RTKs) are key regulatory signaling proteins governing cancer cell growth and metastasis. During the last two decades, several molecules targeting RTKs were used in oncology as a ... [more ▼]

Receptor tyrosine kinases (RTKs) are key regulatory signaling proteins governing cancer cell growth and metastasis. During the last two decades, several molecules targeting RTKs were used in oncology as a first or second line therapy in different types of cancer. However, their effectiveness is limited by the appearance of resistance or adverse effects. In this review, we summarize the main features of RTKs and their inhibitors (RTKIs), their current use in oncology, and mechanisms of resistance. We also describe the technological advances of artificial intelligence, chemoproteomics, and microfluidics in elaborating powerful strategies that could be used in providing more efficient and selective small molecules inhibitors of RTKs. Finally, we discuss the interest of therapeutic combination of different RTKIs or with other molecules for personalized treatments, and the challenge for effective combination with less toxic and off-target effects. [less ▲]

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See detailBRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers
Coussy, F.; El-Botty, R.; Château-Joubert, S. et al

in Science Translational Medicine (2020), 12(532),

Topoisomerase I (TOP1) inhibitors trap TOP1 cleavage complexes resulting in DNA double-strand breaks (DSBs) during replication, which are repaired by homologous recombination (HR). Triple-negative breast ... [more ▼]

Topoisomerase I (TOP1) inhibitors trap TOP1 cleavage complexes resulting in DNA double-strand breaks (DSBs) during replication, which are repaired by homologous recombination (HR). Triple-negative breast cancer (TNBC) could be eligible for TOP1 inhibitors given the considerable proportion of tumors with a defect in HR-mediated repair (BRCAness). The TOP1 inhibitor irinotecan was tested in 40 patient-derived xenografts (PDXs) of TNBC. BRCAness was determined with a single-nucleotide polymorphism (SNP) assay, and expression of Schlafen family member 11 (SLFN11) and retinoblastoma transcriptional corepressor 1 (RB1) was evaluated by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry analyses. In addition, the combination of irinotecan and the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor VE-822 was tested in SLFN11-negative PDXs, and two clinical non-camptothecin TOP1 inhibitors (LMP400 and LMP776) were tested. Thirty-eight percent of the TNBC models responded to irinotecan. BRCAness combined with high SLFN11 expression and RB1 loss identified highly sensitive tumors, consistent with the notion that deficiencies in cell cycle checkpoints and DNA repair result in high sensitivity to TOP1 inhibitors. Treatment by the ATR inhibitor VE-822 increased sensitivity to irinotecan in SLFN11-negative PDXs and abolished irinotecan-induced phosphorylation of checkpoint kinase 1 (CHK1). LMP400 (indotecan) and LMP776 (indimitecan) showed high antitumor activity in BRCA1-mutated or BRCAness-positive PDXs. Last, low SLFN11 expression was associated with poor survival in 250 patients with TNBC treated with anthracycline-based chemotherapy. In conclusion, a substantial proportion of TNBC respond to irinotecan. BRCAness, high SLFN11 expression, and RB1 loss are highly predictive of response to irinotecan and the clinical indenoisoquinoline TOP1 inhibitors. Copyright © 2020 The Authors, some rights reserved. [less ▲]

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See detailStromal integrin alpha11 regulates PDGFR-beta signaling and promotes breast cancer progression.
Primac, Irina ULiege; Maquoi, Erik ULiege; Blacher, Silvia ULiege et al

in Journal of Clinical Investigation (2019), 130

Cancer-associated fibroblasts (CAFs) are key actors in modulating the progression of many solid tumors such as breast cancer (BC). Herein, we identify an integrin alpha11/PDGFRbeta+ CAF subset displaying ... [more ▼]

Cancer-associated fibroblasts (CAFs) are key actors in modulating the progression of many solid tumors such as breast cancer (BC). Herein, we identify an integrin alpha11/PDGFRbeta+ CAF subset displaying tumor-promoting features in BC. In the preclinical MMTV-PyMT mouse model, integrin alpha11-deficiency led to a drastic reduction of tumor progression and metastasis. A clear association between integrin alpha11 and PDGFRbeta was found at both transcriptional and histological levels in BC specimens. High stromal integrin alpha11/PDGFRbeta expression was associated with high grades and poorer clinical outcome in human BC patients. Functional assays using five CAF subpopulations (one murine, four human) revealed that integrin alpha11 promotes CAF invasion and CAF-induced tumor cell invasion upon PDGF-BB stimulation. Mechanistically, integrin alpha11 pro-invasive activity relies on its ability to interact with PDGFRbeta in a ligand-dependent manner and to promote its downstream JNK activation, leading to the production of tenascin C, a pro-invasive matricellular protein. Pharmacological inhibition of PDGFRbeta and JNK impaired tumor cell invasion induced by integrin alpha11-positive CAFs. Collectively, our study uncovers an integrin alpha11-positive subset of pro-tumoral CAFs that exploits PDGFRbeta/JNK signalling axis to promote tumor invasiveness in BC. [less ▲]

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See detailMT4-MMP: The GPI-Anchored Membrane-Type Matrix Metalloprotease with Multiple Functions in Diseases
Yip, Cassandre ULiege; FOIDART, Pierre ULiege; Noël, Agnès ULiege et al

in International Journal of Molecular Sciences (2019), 20 (2)

MT4-MMP (or MMP17) belongs to the Membrane-Type Matrix Metalloproteinase (MT-MMP) family. This family of proteases contributes to extracellular matrix remodeling during several physiological processes ... [more ▼]

MT4-MMP (or MMP17) belongs to the Membrane-Type Matrix Metalloproteinase (MT-MMP) family. This family of proteases contributes to extracellular matrix remodeling during several physiological processes, including embryogenesis, organogenesis, tissue regeneration, angiogenesis, wound healing, and inflammation. MT4-MMP (MMP17) presents unique characteristics compared to other members of the family in terms of sequence homology, substrate specificity, and internalization mode, suggesting distinct physiological and pathological functions. While the physiological functions of MT4-MMP are poorly understood, it has been involved in different pathological processes such as arthritis, cardiovascular disease, and cancer progression. The mt4-mmp transcript has been detected in a large diversity of cancers. The contribution of MT4-MMP to tumor development has been further investigated in gastric cancer, colon cancer, head and neck cancer, and more deeply in breast cancer. Given its contribution to different pathologies, particularly cancers, MT4-MMP represents an interesting therapeutic target. In this review, we examine its biological and structural properties, and we propose an overview of its physiological and pathological functions. [less ▲]

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See detailRewiring of Lipid Metabolism and Storage in Ovarian Cancer Cells after Anti-VEGF Therapy
Curtarello, Matteo; Tognon, Martina; Venturoli, Carolina et al

in Cells (2019)

Anti-angiogenic therapy triggers metabolic alterations in experimental and human tumors, the best characterized being exacerbated glycolysis and lactate production. By using both Liquid Chromatography ... [more ▼]

Anti-angiogenic therapy triggers metabolic alterations in experimental and human tumors, the best characterized being exacerbated glycolysis and lactate production. By using both Liquid Chromatography-Mass Spectrometry (LC-MS) and Nuclear Magnetic Resonance (NMR) analysis, we found that treatment of ovarian cancer xenografts with the anti-Vascular Endothelial Growth Factor (VEGF) neutralizing antibody bevacizumab caused marked alterations of the tumor lipidomic profile, including increased levels of triacylglycerols and reduced saturation of lipid chains. Moreover, transcriptome analysis uncovered up-regulation of pathways involved in lipid metabolism. These alterations were accompanied by increased accumulation of lipid droplets in tumors. This phenomenon was reproduced under hypoxic conditions in vitro, where it mainly depended from uptake of exogenous lipids and was counteracted by treatment with the Liver X Receptor (LXR)-agonist GW3965, which inhibited cancer cell viability selectively under reduced serum conditions. This multi-level analysis indicates alterations of lipid metabolism following anti-VEGF therapy in ovarian cancer xenografts and suggests that LXR-agonists might empower anti-tumor e ects of bevacizumab. [less ▲]

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See detailExpression of MT4-MMP, EGFR, and RB in Triple-Negative Breast Cancer Strongly Sensitizes Tumors to Erlotinib and Palbociclib Combination Therapy.
FOIDART, Pierre ULiege; Yip, Cassandre ULiege; Radermacher, Jean et al

in Clinical Cancer Research (2019)

Abstract Purpose: Here, we investigated the clinical relevance of an unprecedented combination of three biomarkers in triple-negative breast cancer (TNBC), both in human samples and in patient-derived ... [more ▼]

Abstract Purpose: Here, we investigated the clinical relevance of an unprecedented combination of three biomarkers in triple-negative breast cancer (TNBC), both in human samples and in patient-derived xenografts of TNBC (PDX-TNBC): EGFR, its recently identified partner (MT4-MMP), and retinoblastoma protein (RB).Experimental Design: IHC analyses were conducted on human and PDX-TNBC samples to evaluate the production of the three biomarkers. The sensitivity of cancer cells expressing or not MT4-MMP to anti-EGFR (erlotinib) or anti-CDK4/6 inhibitor (palbociclib) was evaluated in vitro in 2D and 3D proliferation assays and in vivo using xenografts and PDX-TNBC displaying different RB, MT4-MMP, and EGFR status after single (erlotinib or palbociclib) or combined (erlotinib + palbociclib) treatments.Results: EGFR and MT4-MMP were coexpressed in >70% of TNBC samples and PDX-TNBC, among which approximately 60% maintained RB expression. Notably, approximately 50% of all TNBC and PDX-TNBC expressed the three biomarkers. Single erlotinib and palbociclib treatments drastically reduced the in vitro proliferation of cells expressing EGFR and MT4-MMP when compared with control cells. Both TNBC xenografts and PDX expressing MT4-MMP, EGFR, and RB, but not PDX-TNBC with RB loss, were sensitive to erlotinib and palbociclib with an additive effect of combination therapy. Moreover, this combination was efficient in another PDX-TNBC expressing the three biomarkers and resistant to erlotinib alone.Conclusions: We defined a new association of three biomarkers (MT4-MMP/EGFR/RB) expressed together in 50% of TNBC and demonstrated its usefulness to predict the TNBC response to anti-EGFR and anti-CDK4/6 drugs used in single or combined therapy. [less ▲]

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See detailMetabolic adaptation to anti-angiogenic therapy
Sounni, Nor Eddine ULiege

Conference (2018, October 15)

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See detailMetabolic adaptation of tumor to hypoxia induced by anti-angiogenic therapy
Sounni, Nor Eddine ULiege

Conference (2018, March 16)

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See detailMT4-MMP, EGFR and RB expressions are predictive biomarkers of response to Erlotinib-Palbociclib combination in TNBC
FOIDART, Pierre ULiege; Yip, Cassandre ULiege; Radermacher, Jean et al

Conference (2018, February 24)

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See detailExpression of MT4-MMP, EGFR and Rb in triple negative breast cancers strongly sensitizes tumors to Erlotinib and Palbociclib combination therapy
FOIDART, Pierre ULiege; Yip, Cassandre ULiege; Radermacher, Jean et al

Scientific conference (2018, January 27)

Triple negative breast cancer (TNBC) comprises heterogeneous tumors displaying an aggressive pattern of progression and metastasis. The standard systemic treatment relies entirely on chemotherapy. While ... [more ▼]

Triple negative breast cancer (TNBC) comprises heterogeneous tumors displaying an aggressive pattern of progression and metastasis. The standard systemic treatment relies entirely on chemotherapy. While epidermal growth factor receptor (EGFR) is frequently over-expressed in TNBC, targeted therapies against EGFR did not show clinical benefit. Recently, we demonstrated that EGFR interacts with MT4-MMP, the membrane-type 4 matrix metalloproteinase in TNBC. Also, based on an immunohistochemistry (IHC) analysis we reported that EGFR and MT4-MMP are co-expressed in 79 % of human TNBC samples. Here, we identified MT4-MMP/EGFR axis as an important driver of cancer cell proliferation through CDK4 activation and retinoblastoma protein (Rb) inactivation. Finally, we investigated the significance of targeting EGFR and CDK4 in TNBC expressing MT4-MMP and EGFR. [less ▲]

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