L'objectif de ce cours est de fournir une vue d'ensemble pratique et actualisée des dernières recherches et des développements cliniques dans le domaine du cancer urothélial, y compris les cancers de la vessie invasifs et non invasifs sur le plan musculaire, les carcinomes urothéliaux des voies urinaires supérieures et leurs métastases. Ce faisant, nous visons à : a) promouvoir une compréhension consensuelle des stratégies optimales actuelles de traitement de ces maladies, b) fournir des connaissances pratiques et une perspective clinique des maladies et de leur traitement, c) promouvoir une meilleure compréhension mécaniste des maladies et des méthodologies utilisées pour les étudier, et d) fournir une perspective industrielle pour partager la façon dont les nouveaux traitements sont développés.

Life is highly dynamic relaying on a myriad of carefully orchestrated processes with strict spatial and temporal control. To decipher cellular functions and, in turn, address complex biological questions is necessary to have precise control. In my group, we pursue such the dream of achieving a molecularly precise understanding of biology to address the problems arising from misregulation. For this purpose, we focus on the design of innovative chemical biology tools. In particular, optochemical tools based on the synthesis of photosensitive molecules such as fluorophores, photosensitizers and photoswitches enabled us the desired conditional modulation in disease-related processes. In this talk I will make a brief summary about our projects where fluorophores have demonstrated the possibility of efficiently labelled multidrug resistant bacteria1 as well as the development of bioorthogonally activatable photosensitizers for photodynamic therapy.2-3 However, the main part of this presentation will deal with the use of photoswitches for light-controllable gene expression.

All cells in an organism contain the same DNA sequence but vary greatly in gene expression. Epigenetics deals with these phenotype changes that retains the same DNA sequence. Importantly, misregulation of these epigenetic processes is implicated in the pathophysiology of numerous human diseases,4 including: cancer, autoimmune disorders and neurodegenerative disease. Therefore, epigenetic regulation is at the core of both natural and pathological states. The current available methods do not have sufficient spatiotemporal resolution to deal with the challenges of targeting the dynamic epigenome. We and others 5 envision that light could offer new possibilities and achieve molecular functionality. Reversible photoswitches, which have demonstrated their potential in diverse areas such as material science, have hardly implemented as genome regulators. Modulating the epigenome to tune transcription profiles, and cellular phenotypes in a programmable manner is of wide interest, and may ultimately lead to novel epigenetics-based therapeutics. Here, I will present our journey to achieve in vivo manipulation, 6-9 as well as our most recent work where photoswitches can control splicing and, in turn, gene expression.10

References

1. Schulte, L. N.; Heinrich, B.; Janga, H.; Schmeck, B. T.; Vazquez, O., A Far-Red Fluorescent DNA Binder for Interaction Studies of Live Multidrug-Resistant Pathogens and Host Cells. Angew Chem Int Ed Engl 2018, 57 (36), 11564-11568.

2. Linden, G.; Zhang, L.; Pieck, F.; Linne, U.; Kosenkov, D.; Tonner, R.; Vazquez, O., Conditional Singlet Oxygen Generation through a Bioorthogonal DNA-targeted Tetrazine Reaction. Angew Chem Int Ed Engl 2019, 58 (37), 12868-12873.

3. Linden, G.; Vazquez, O., Bioorthogonal Turn-On BODIPY-Peptide Photosensitizers for Tailored Photodynamic Therapy. Chemistry 2020, 26 (44), 10014-10023.

4. Portela, A.; Esteller, M., Epigenetic modifications and human disease. Nat Biotechnol 2010, 28 (10), 1057-68.

5. Hartmann, D.; Smith, J. M.; Mazzotti, G.; Chowdhry, R.; Booth, M. J., Controlling gene expression with light: a multidisciplinary endeavour. Biochem Soc Trans 2020, 48 (4), 1645-1659.

6. Albert, L.; Xu, J.; Wan, R.; Srinivasan, V.; Dou, Y.; Vazquez, O., Controlled inhibition of methyltransferases using photoswitchable peptidomimetics: towards an epigenetic regulation of leukemia. Chem Sci 2017, 8 (6), 4612-4618.

7. Heinrich, B.; Bouazoune, K.; Wojcik, M.; Bakowsky, U.; Vazquez, O., ortho-Fluoroazobenzene derivatives as DNA intercalators for photocontrol of DNA and nucleosome binding by visible light. Org Biomol Chem 2019, 17 (7), 1827-1833.

8. Albert, L.; Penalver, A.; Djokovic, N.; Werel, L.; Hoffarth, M.; Ruzic, D.; Xu, J.; Essen, L. O.; Nikolic, K.; Dou, Y.; Vazquez, O., Modulating Protein-Protein Interactions with Visible-Light-Responsive Peptide Backbone Photoswitches. Chembiochem 2019, 20 (11), 1417-1429.

9. Albert, L.; Nagpal, J.; Steinchen, W.; Zhang, L.; Werel, L.; Djokovic, N.; Ruzic, D.; Hoffarth, M.; Xu, J.; Kaspareit, J.; Abendroth, F.; Royant, A.; Bange, G.; Nikolic, K.; Ryu, S.; Dou, Y.; Essen, L. O.; Vazquez, O., Bistable Photoswitch Allows in Vivo Control of Hematopoiesis. ACS Cent Sci 2022, 8 (1), 57-66.

10.  Zhang, L.; Xie, X.; Djokovic, N.; Nikolic, K.; Kosenkov, D.; Abendroth, F.; Vazquez, O., Reversible Control of RNA Splicing by Photoswitchable Small Molecules. J Am Chem Soc 2023, 145 (23), 12783-12792.