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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 detailAsthma-related inflammation promotes lung metastasis of breast cancer cells through CCL11–CCR3 pathway
BEKAERT, Sandrine ULiege; Rocks, Natacha ULiege; Vanwinge, Céline ULiege et al

in Respiratory Research (2021), 22(1), 61

Background: Mechanisms that preclude lung metastasis are still barely understood. The possible consequences of allergic airways inflammation on cancer dissemination were studied in a mouse model of breast ... [more ▼]

Background: Mechanisms that preclude lung metastasis are still barely understood. The possible consequences of allergic airways inflammation on cancer dissemination were studied in a mouse model of breast cancer. Methods: Balb/c mice were immunized and daily exposed to ovalbumin (OVA) from day 21. They were subcutane- ously injected with 4T1 mammary tumor cells on day 45 and sacrificed on day 67. Lung metastases were measured by biophotonic imaging (IVIS 200 Imaging System) and histological measurement of tumor area (Cytomine software). Effects of CCL11 were assessed in vivo by intratracheal instillations of recCCL11 and in vitro using Boyden chambers. CCR3 expression on cell surface was assessed by flow cytometry. Results: The extent of tumor metastases was significantly higher in lungs of OVA-exposed mice and increased levels of CCL11 expression were measured after OVA exposure. Migration of 4T1 cells and neutrophils was stimulated in vitro and in vivo by recCCL11. 4T1 cells and neutrophils express CCR3 as shown by flow cytometry and a selective CCR3 antagonist (SB-297006) inhibited the induction of 4T1 cells migration and proliferation in response to recCCL11. Conclusions: Allergic inflammation generated by exposure to allergens triggers the implantation of metastatic cells from primary breast tumor into lung tissues plausibly in a CCL11–CCR3-dependent manner. This indicates that asthma related inflammation in lungs might be a risk factor for lung metastasis in breast cancer patients. [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 detailIntravitreal injection of anti-miRs against miR-142-3p reduces angiogenesis and microglia activation in a mouse model of laser-induced choroidal neovascularization.
Roblain, Quentin ULiege; Louis, Thomas ULiege; Yip, Cassandre ULiege et al

in Aging (2021), 13

Age-related macular degeneration (AMD) is a worldwide leading cause of blindness affecting individuals over 50 years old. The most aggressive form, wet AMD, is characterized by choroidal ... [more ▼]

Age-related macular degeneration (AMD) is a worldwide leading cause of blindness affecting individuals over 50 years old. The most aggressive form, wet AMD, is characterized by choroidal neovascularization (CNV) and inflammation involving microglia recruitment. By using a laser-induced CNV mouse model, we provide evidence for a key role played by miR-142-3p during CNV formation. MiR-142-3p was overexpressed in murine CNV lesions and its pharmacological inhibition decreased vascular and microglia densities by 46% and 30%, respectively. Consistently, miR-142-3p overexpression with mimics resulted in an increase of 136% and 126% of blood vessels and microglia recruitment. Interestingly, miR-142-3p expression was linked to the activation state of mouse microglia cells as determined by morphological analysis (cell solidity) through a computational method. In vitro, miR-142-3p overexpression in human microglia cells (HMC3) modulated microglia activation, as shown by CD68 levels. Interestingly, miR142-3p modulation also regulated the production of VEGF-A, the main pro-angiogenic factor. Together, these data strongly support the unprecedented importance of miR-142-3p-dependent vascular-inflammation axis during CNV progression, through microglia activation. [less ▲]

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See detailTumor exposed-lymphatic endothelial cells promote primary tumor growth via IL6.
Van de Velde, Maureen; Ebroin, Marie ULiege; Durré, Tania ULiege et al

in Cancer Letters (2021), 497

Solid tumors are composed of tumor cells and stromal cells including lymphatic endothelial cells (LEC), which are mainly viewed as cells forming lymphatic vessels involved in the transport of metastatic ... [more ▼]

Solid tumors are composed of tumor cells and stromal cells including lymphatic endothelial cells (LEC), which are mainly viewed as cells forming lymphatic vessels involved in the transport of metastatic and immune cells. We here reveal a new mechanism by which tumor exposed-LEC (teLEC) exert mitogenic effects on tumor cells. Our conclusions are supported by morphological and molecular changes induced in teLEC that in turn enhance cancer cell invasion in 3D cultures and tumor cell proliferation in vivo. The characterization of teLEC secretome by RNA-Sequencing and cytokine array revealed that interleukine-6 (IL6) is one of the most modulated molecules in teLEC, whose production was negligible in unexposed LEC. Notably, neutralizing anti-human IL6 antibody abrogated teLEC-mediated mitogenic effects in vivo, when LEC were mixed with tumor cells in the ear sponge assay. We here assign a novel function to teLEC that is beyond their role of lymphatic vessel formation. This work highlights a new paradigm, in which teLEC exert "fibroblast-like properties", contribute in a paracrine manner to the control of tumor cell properties and are worth considering as key stromal determinant in future studies. [less ▲]

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See detailPyruvate dehydrogenase kinase/lactate axis: a therapeutic target for neovascular age-related macular degeneration identified by metabolomics
LAMBERT, Vincent ULiege; hansen, Sylvain; Schoumacher, Matthieu ULiege et al

in Journal of Molecular Medicine (2020)

Neovascular age-related macular degeneration (nAMD) is the leading cause of blindness in aging populations. Here, we applied metabolomics to human sera of patients with nAMD during an active (exudative ... [more ▼]

Neovascular age-related macular degeneration (nAMD) is the leading cause of blindness in aging populations. Here, we applied metabolomics to human sera of patients with nAMD during an active (exudative) phase of the pathology and found higher lactate levels and a shift in the lipoprotein profile (increased VLDL-LDL/HDL ratio). Similar metabolomics changes were detected in the sera of mice subjected to laser-induced choroidal neovascularization (CNV). In this experimental model, we provide evidence for two sites of lactate production: first, a local one in the injured eye, and second a systemic site associated with the recruitment of bone marrow–derived inflammatory cells. Mechanistically, lactate promotes the angiogenic response and M2-like macrophage accumulation in the eyes. The therapeutic potential of our findings is demonstrated by the pharmacological control of lactate levels through pyruvate dehydrogenase kinase (PDK) inhibition by dichloroacetic acid (DCA). Mice treated with DCA exhibited normalized lactate levels and lipoprotein profiles, and inhibited CNV formation. Collectively, our findings implicate the key role of the PDK/lactate axis in AMD pathogenesis and reveal that the regulation of PDK activity has potential therapeutic value in this ocular disease. The results indicate that the lipoprotein profile is a traceable pattern that is worth considering for patient follow-up. [less ▲]

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See detailReciprocal Interplay Between Fibrillar Collagens and Collagen-Binding Integrins: Implications in Cancer Progression and Metastasis
Bourgot, Isabelle ULiege; Primac, Irina; Louis, Thomas ULiege et al

in Frontiers in Oncology (2020), 10(1488),

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See detailRole of Lipid droplets in cancer progression and resistance to anti-cancer drugs.
Wery, Coline ULiege; Godfroid, Adrien; LUIS, Géraldine ULiege et al

Poster (2020, February 07)

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See detailLiposomes and drug-in-cyclodextrin-in-liposomes formulations encapsulating 17β-estradiol: an innovative drug delivery system that prevents the activation of the membrane-initiated steroid signaling (MISS) of estrogen receptor α
Gallez, Anne ULiege; Palazzo, Claudio ULiege; Blacher, Silvia ULiege et al

in International Journal of Pharmaceutics (2020), 573

The encapsulation into liposomes of several types of molecules presents the advantages to protect the activity of these molecules and to target specific tissues. Nevertheless, a major obstacle remains the ... [more ▼]

The encapsulation into liposomes of several types of molecules presents the advantages to protect the activity of these molecules and to target specific tissues. Nevertheless, a major obstacle remains the incomplete understanding of nano-bio interactions. Specifically, the impact that inclusion of drug into liposomes or of drug-in-cyclodextrin-in liposomes (DCL) could have on the molecular and cellular mechanism of drug action is largely unknown. As a proof of concept, we evaluated the impact of 17β-estradiol (E2) included into liposomes or DCL on estrogen receptor (ER)α signaling pathways. Indeed, ERα relays the pleiotropic actions of E2 in physiology and pathophysiology through two major pathways: (1) the genomic/nuclear effects associated to the transcriptional activity of the ERα and (2) the rapid/nongenomic/membrane-initiated steroid signaling (MISS) effects related to the induction of fast signaling pathways occurring when ERα is anchored to the plasma membrane. We evidenced that the inclusion of E2 into liposomes (Lipo-E2) or into DCL (DCL-E2) prevented the activation of the rapid/nongenomic/extranuclear/MISS pathway of ERα, while the activation of the genomic/nuclear pathway was maintained. These results support that Lipo-E2 and DCL-E2 could be a useful tool to delineate the complex molecular mechanisms associated to ERα. In conclusion, this study supports the notion that inclusion of drugs into liposomes or DCL could modify some specific pathways of their molecular and cellular mechanisms of action. These results emphasized that attention should be paid to nano-bio interactions induced by the use of nanovectors in medicine. [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 detailNew Insight into exudative Age-related Macular Degeneration (AMD): A Metabolomics Approach
Schoumacher, Matthieu ULiege; LAMBERT, Vincent ULiege; Hansen, Sylvain et al

Conference (2019, December 11)

Age-related macular degeneration (AMD) is common disease and leading causes of vision loss among people aged 50 and older. Late-stage AMD (called exudative) is characterized by choroidal ... [more ▼]

Age-related macular degeneration (AMD) is common disease and leading causes of vision loss among people aged 50 and older. Late-stage AMD (called exudative) is characterized by choroidal neovascularization (CNV) and results in complete loss of central vision acuity leading to severe visual impairment and legal blindness. Currently, AMD diagnosis relies on ophthalmologic exams and treatments of the exudative form using anti-angiogenic drugs targeting vascular endothelial growth factors (VEGF). Despite these advances, the identification of therapeutic treatments and related biomarkers are essentials. In this study, we applied a NMR-based metabolomics approach on a cohort of AMD patients and on a laser-induced murine CNV experimental model that mimics the pathology angiogenesis’s development phase. Sera from controls and AMD patients (in active and non-active pathology’s phases) and from induced and non-induced mice have been collected and submitted to a metabolomics study, using a multivariate approach. This approach allows differentiation between active and non-active AMD patients and between laser-induced and the control mice groups. Moreover, the discriminating spectral zones are the same in both human and mice’s models, leading to the emergence of putative biomarkers of the exudative AMD. Among those, lactate and lipoprotein emerges as a key metabolite in both settings. Here we suggest metabolomics as a novel option for patients’ follow-up and new therapeutical strategies targeting lactate metabolism for AMD. [less ▲]

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See detailFrom Metabolomics Study of Age Related Macular Degeneration (AMD) to the Development of New Pyruvate Dehydrogenase Kinase (PDK) Inhibitors
Arslan, Deniz ULiege; LAMBERT, Vincent ULiege; Noël, Agnès ULiege et al

Poster (2019, December 11)

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population of industrialized countries. This blindness results from the deterioration of the macula, a small zone of ... [more ▼]

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population of industrialized countries. This blindness results from the deterioration of the macula, a small zone of the retina specialized for the high-acuity vision. Exudative AMD, called “wet AMD”, is characterized by the formation of new blood vessels growing under the retina according to a process named choroidal neovascularization (CNV). Currently, the aetiology and pathogenesis of wet AMD remain unclear. Nevertheless, a recent metabolomics study performed on the serum of “wet” AMD patients and on a CNV murine model, that mimics the effect of “wet” AMD, has demonstrated that lactate is clearly involved in the severity and the evolution of the pathology and of CNV. According to this study, we suggest a new therapeutic approach of AMD based on the normalization of blood lactate level. The modulation of the lactate plasma concentration by treatment of the animals with synthetic compounds and more specifically Pyruvate Dehydrogenase Kinase (PDK) inhibitors significantly decrease the CNV. Starting from these results, development of new PDK inhibitors could open the way to innovative treatment for AMD disease. [less ▲]

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See detailImpact of cancer associated fibroblasts-derived cathepsin B on breast cancer progression
Bourgot, Isabelle ULiege; Louis, Thomas ULiege; Kasabova, Mariana et al

Poster (2019, September 20)

Tumors arise in a complex ecosystem gover ned by interactions established between cancer cells and the microenvironment. This one is constituted on one side by a multitude of different non-cancerous cell ... [more ▼]

Tumors arise in a complex ecosystem gover ned by interactions established between cancer cells and the microenvironment. This one is constituted on one side by a multitude of different non-cancerous cell types (e.g.: stromal and immune cells) and on the other side by components of the extracellular matrix. During cancerogenesis fibroblasts are activated and differenciated into cancer associated fibroblasts (CAFs). Nevertheless, the precise functions of CAFs in cancer progression are not fully understood. Among proteases implicated in both ECM remodeling and cancer progression, cathepsin B (Ctsb), a lysosomial cystein protease, has been detected in cancer cells and in tumor-associated macrophages. Ctsb expression is associated with a poor prognosis in breast cancer patients. However, the contribution of CAF-derived Ctsb to tumor progression is unknown. By using the MMTV-PyMT mouse model of breast cancer, our preliminary data reveal that CAFs express Ctsb at higher levels than cancer cells. Our data show that Ctsb deficiency impairs the capacity of CAFs to interact with collagen fibers and strongly diminishes the migration of CAFs in a 3D spheroid model. Further more, we demonstrate that the invasion of Ctsb-/- CAFs is restored upon addition of conditioned medium collected from WT CAFs but Further more, the invasion of Ctsb-/- CAFs is restored upon addition of conditioned medium collected from wild-type (WT) CAFs but also by durotaxis or by deletion of Cathepsin Z (Ctsz). Collectively these data suggest that Ctsb represents a key regulator of the complex cross-talk established between CAFs, the ECM and cancer cells. [less ▲]

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See detailImpact of cancer associated fibroblasts-derived cathepsin B on breast cancer progression
Bourgot, Isabelle ULiege; Louis, Thomas; Kasabova, Mariana et al

Conference (2019, September 19)

Tumors arise in a complex ecosystem gover ned by interactions established between cancer cells and the microenvironment. This one is constituted on one side by a multitude of different non-cancerous cell ... [more ▼]

Tumors arise in a complex ecosystem gover ned by interactions established between cancer cells and the microenvironment. This one is constituted on one side by a multitude of different non-cancerous cell types (e.g.: stromal and immune cells) and on the other side by components of the extracellular matrix. During cancerogenesis fibroblasts are activated and differenciated into cancer associated fibroblasts (CAFs). Nevertheless, the precise functions of CAFs in cancer progression are not fully understood. Among proteases implicated in both ECM remodeling and cancer progression, cathepsin B (Ctsb), a lysosomial cystein protease, has been detected in cancer cells and in tumor-associated macrophages. Ctsb expression is associated with a poor prognosis in breast cancer patients. However, the contribution of CAF-derived Ctsb to tumor progression is unknown. By using the MMTV-PyMT mouse model of breast cancer, our preliminary data reveal that CAFs express Ctsb at higher levels than cancer cells. Our data show that Ctsb deficiency impairs the capacity of CAFs to interact with collagen fibers and strongly diminishes the migration of CAFs in a 3D spheroid model. Further more, we demonstrate that the invasion of Ctsb-/- CAFs is restored upon addition of conditioned medium collected from WT CAFs but Further more, the invasion of Ctsb-/- CAFs is restored upon addition of conditioned medium collected from wild-type (WT) CAFs but also by durotaxis or by deletion of Cathepsin Z (Ctsz). Collectively these data suggest that Ctsb represents a key regulator of the complex cross-talk established between CAFs, the ECM and cancer cells. [less ▲]

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See detailRole of cancer cells associated lipid droplets in adaptation to hypoxia and tumor microenvironmental stresses.
Wery, Coline ULiege; Godfroid, Adrien; LUIS, Géraldine ULiege et al

Poster (2019, September 06)

Detailed reference viewed: 29 (6 ULiège)