Publications by authors named "Charline Degavre"

5 Publications

  • Page 1 of 1

Acidosis-Induced TGF-β2 Production Promotes Lipid Droplet Formation in Dendritic Cells and Alters Their Potential to Support Anti-Mesothelioma T Cell Response.

Cancers (Basel) 2020 May 19;12(5). Epub 2020 May 19.

Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, B-1200 Brussels, Belgium.

For poorly immunogenic tumors such as mesothelioma there is an imperious need to understand why antigen-presenting cells such as dendritic cells (DCs) are not prone to supporting the anticancer T cell response. The tumor microenvironment (TME) is thought to be a major contributor to this DC dysfunction. We have reported that the acidic TME component promotes lipid droplet (LD) formation together with epithelial-to-mesenchymal transition in cancer cells through autocrine transforming growth factor-β2 (TGF-β2) signaling. Since TGF-β is also a master regulator of immune tolerance, we have here examined whether acidosis can impede immunostimulatory DC activity. We have found that exposure of mesothelioma cells to acidosis promotes TGF-β2 secretion, which in turn leads to LD accumulation and profound metabolic rewiring in DCs. We have further documented how DCs exposed to the mesothelioma acidic milieu make the anticancer vaccine less efficient in vivo, with a reduced extent of both DC migratory potential and T cell activation. Interestingly, inhibition of TGF-β2 signaling and diacylglycerol O-acyltransferase (DGAT), the last enzyme involved in triglyceride synthesis, led to a significant restoration of DC activity and anticancer immune response. In conclusion, our study has identified that acidic mesothelioma milieu drives DC dysfunction and altered T cell response through pharmacologically reversible TGF-β2-dependent mechanisms.
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http://dx.doi.org/10.3390/cancers12051284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281762PMC
May 2020

Photodynamic Therapy-Based Dendritic Cell Vaccination Suited to Treat Peritoneal Mesothelioma.

Cancers (Basel) 2020 Feb 27;12(3). Epub 2020 Feb 27.

Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, 1200 Brussels, Belgium.

The potential of dendritic cell (DC)-based immunotherapy to treat cancer is, nowadays, well documented. Still, the clinical success of immune checkpoint inhibitors has dampened the interest in anticancer DC vaccination. For highly life-threatening tumors that are regarded as nonimmunogenic, such as mesothelioma, however, T helper 1 immunity-biased DC-based immunotherapy could still represent an attractive strategy. In this study, we took advantage of photodynamic therapy (PDT) to induce immunogenic cell death to generate mesothelioma cell lysates for DC priming and evaluated such a vaccine to treat peritoneal mesothelioma. We found that the white light in vitro activation of the photosensitizer OR141 led to mesothelioma cell death, together with the release of bona fide danger signals that promote DC maturation. The administration of a PDT-based DC vaccine to mice bearing peritoneal mesothelioma led to highly significant survival when compared with sham or control animals treated with anti-CTLA4 antibodies. This was further supported by a strong CD8 and CD4 T cell response, characterized by an increased proliferation, cytotoxic activities and the expression of activation markers, including interferon gamma (IFN). Moreover, the PDT-based DC vaccine led to a significant increase in IFN T cells infiltered within mesothelioma, as determined by flow cytometry and immunohistochemistry. Finally, in vivo tracking of intraperitoneally administered DCs led us to document rapid chemotaxis towards tumor-occupied lymphatics (vs. lipopolysaccharide (LPS)-treated DC). DCs pulsed with PDT-killed mesothelioma cells also exhibited a significant increase in CCR7 receptors, together with an intrinsic capacity to migrate towards the lymph nodes. Altogether, these results indicate that PDT-based DC vaccination is particularly suited to induce a potent immune response against peritoneal mesothelioma.
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http://dx.doi.org/10.3390/cancers12030545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139796PMC
February 2020

Structure-Activity Relationships (SARs) of α-Ketothioamides as Inhibitors of Phosphoglycerate Dehydrogenase (PHGDH).

Pharmaceuticals (Basel) 2020 Jan 22;13(2). Epub 2020 Jan 22.

Medicinal Chemistry Research Group (CMFA), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain, 1200 Brussels, Belgium.

For many years now, targeting deregulation within cancer cells' metabolism has appeared as a promising strategy for the development of more specific and efficient cancer treatments. Recently, numerous reports highlighted the crucial role of the serine synthetic pathway, and particularly of the phosphoglycerate dehydrogenase (PHGDH), the first enzyme of the pathway, to sustain cancer progression. Yet, because of very weak potencies usually in cell-based settings, the inhibitors reported so far failed to lay ground on the potential of this approach. In this paper, we report a structure-activity relationship study of a series of α-ketothioamides that we have recently identified. Interestingly, this study led to a deeper understanding of the structure-activity relationship (SAR) in this series and to the identification of new PHGDH inhibitors. The activity of the more potent compounds was confirmed by cellular thermal shift assays and in cell-based experiments. We hope that this research will eventually provide a new entry point, based on this promising chemical scaffold, for the development of therapeutic agents targeting PHGDH.
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http://dx.doi.org/10.3390/ph13020020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168936PMC
January 2020

TGFβ2-induced formation of lipid droplets supports acidosis-driven EMT and the metastatic spreading of cancer cells.

Nat Commun 2020 01 23;11(1):454. Epub 2020 Jan 23.

Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, 57 Avenue Hippocrate B1.57.04, B-1200, Brussels, Belgium.

Acidosis, a common characteristic of the tumor microenvironment, is associated with alterations in metabolic preferences of cancer cells and progression of the disease. Here we identify the TGF-β2 isoform at the interface between these observations. We document that acidic pH promotes autocrine TGF-β2 signaling, which in turn favors the formation of lipid droplets (LD) that represent energy stores readily available to support anoikis resistance and cancer cell invasiveness. We find that, in cancer cells of various origins, acidosis-induced TGF-β2 activation promotes both partial epithelial-to-mesenchymal transition (EMT) and fatty acid metabolism, the latter supporting Smad2 acetylation. We show that upon TGF-β2 stimulation, PKC-zeta-mediated translocation of CD36 facilitates the uptake of fatty acids that are either stored as triglycerides in LD through DGAT1 or oxidized to generate ATP to fulfill immediate cellular needs. We also address how, by preventing fatty acid mobilization from LD, distant metastatic spreading may be inhibited.
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http://dx.doi.org/10.1038/s41467-019-14262-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978517PMC
January 2020

Perforin Promotes Amyloid Beta Internalisation in Neurons.

Mol Neurobiol 2017 03 16;54(2):874-887. Epub 2016 Jan 16.

Division for Neurogeriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Center for Alzheimer Research, Karolinska Institutet, Novum 5th floor, Huddinge, 141 57, Sweden.

Studies on the mechanisms of neuronal amyloid-β (Aβ) internalisation are crucial for understanding the neuropathological progression of Alzheimer's disease (AD). We here investigated how extracellular Aβ peptides are internalised and focused on three different pathways: (i) via endocytic mechanisms, (ii) via the receptor for advanced glycation end products (RAGE) and (iii) via the pore-forming protein perforin. Both Aβ and Aβ were internalised in retinoic acid differentiated neuroblastoma (RA-SH-SY5Y) cells. A higher concentration was required for Aβ (250 nM) compared with Aβ (100 nM). The internalised Aβ showed a dot-like pattern of distribution whereas Aβ accumulated in larger and distinct formations. By confocal microscopy, we showed that Aβ and Aβ co-localised with mitochondria, endoplasmic reticulum (ER) and lysosomes. Aβ treatment of human primary cortical neurons (hPCN) confirmed our findings in RA-SH-SY5Y cells, but hPCN were less sensitive to Aβ; therefore, a 20 (Aβ) and 50 (Aβ) times higher concentration was needed for inducing uptake. The blocking of endocytosis completely inhibited the internalisation of Aβ peptides in RA-SH-SY5Y cells and hPCN, indicating that this is a major pathway by which Aβ enters the cells. In addition, the internalisation of Aβ, but not Aβ, was reduced by 55 % by blocking RAGE. Finally, for the first time we showed that pore formation in cell membranes by perforin led to Aβ internalisation in hPCN. Understanding how Aβ is internalised sheds light on the pathological role of Aβ and provides further ideas of inhibitory strategies for preventing Aβ internalisation and the spreading of neurodegeneration in AD.
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http://dx.doi.org/10.1007/s12035-016-9685-9DOI Listing
March 2017