From Pediatric Cancer Metabolism to Metabolic Regulation of Translation
Event details
| Date | 28.01.2025 |
| Hour | 10:00 › 11:00 |
| Speaker | Raphael J. Morscher, M.D., Ph.D., University Children's Hospital, Zurich (CH) |
| Location | Online |
| Category | Conferences - Seminars |
| Event Language | English |
ONE-DAY METABOLISM MINI-SYMPOSIUM
(talk two / previous talk / next talk)
Abstract:
An organized metabolism forms the foundation of life. Even for complex organisms, such as humans, the space of metabolic operation is relatively well defined. Advances in mass spectrometry allow to move from studying single metabolic reactions to a global understanding of the metabolic network. Here I give an insight on how our lab integrates stable isotope tracing and mass spectrometry to understand metabolic vulnerabilities in cancers and the crosstalk of metabolic networks in an in vivo setting. We then take a deep dive in understanding the interplay of metabolism and translation in neuroblastoma, a highly lethal childhood tumor derived from differentiation-arrested neural crest cells. Like all cancers, its growth is fueled by metabolites obtained from either circulation or local biosynthesis. Neuroblastomas depend on local polyamine biosynthesis, with the inhibitor difluoromethylornithine showing clinical activity. We show that such inhibition can be augmented by restriction of upstream amino acid substrates, leading to disruption of oncogenic protein translation, tumor differentiation, and profound survival gains in the TH-MYCN mouse model. Specifically, an arginine/proline-free diet decreases the polyamine precursor ornithine and augments tumor polyamine depletion by difluoromethylornithine. This polyamine depletion causes ribosome stalling, unexpectedly specifically at adenosine-ending codons. Such codons are selectively enriched in cell cycle genes and low in neuronal differentiation genes. Thus, impaired translation of these codons, induced by the diet-drug combination, favors a pro-differentiation proteome. These results suggest that the genes of specific cellular programs have evolved hallmark codon usage preferences that enable coherent translational rewiring in response to metabolic stresses, and that this process can be targeted to activate differentiation of pediatric cancers.
Bio:
Raphael J. Morscher is a pediatric oncologist and principal investigator at the University of Zurich. His main research interests are in understanding personalized metabolic programs in pediatric cancers and fundamental principles in metabolic regulation of translation. Raphael grew up in Austria and received his MD and PhD from the Paracelsus Medical University in Salzburg. During his PhD he studied reprogramming of metabolism neuroblastoma with Barbara Kofler. In 2016 he moved to Princeton for a postdoctoral fellowship with Joshua Rabinowitz to develop in vivo stable isotope tracing approaches for the study of metabolic operation in health and disease. It was also at that time his work on folate-dependent tRNA modifications sparked interest to better understand how metabolism regulates protein translation at the tRNA /mRNA intersection. In 2022 Raphael established his own research group passionate about spanning from fundamental principles in metabolism to applications in the human system. When not studying metabolism, Raphael is often found on his bike or outside enjoying nature with his family.
Zoom link for attending remotely, if needed: https://epfl.zoom.us/j/68708003718
(talk two / previous talk / next talk)
Abstract:
An organized metabolism forms the foundation of life. Even for complex organisms, such as humans, the space of metabolic operation is relatively well defined. Advances in mass spectrometry allow to move from studying single metabolic reactions to a global understanding of the metabolic network. Here I give an insight on how our lab integrates stable isotope tracing and mass spectrometry to understand metabolic vulnerabilities in cancers and the crosstalk of metabolic networks in an in vivo setting. We then take a deep dive in understanding the interplay of metabolism and translation in neuroblastoma, a highly lethal childhood tumor derived from differentiation-arrested neural crest cells. Like all cancers, its growth is fueled by metabolites obtained from either circulation or local biosynthesis. Neuroblastomas depend on local polyamine biosynthesis, with the inhibitor difluoromethylornithine showing clinical activity. We show that such inhibition can be augmented by restriction of upstream amino acid substrates, leading to disruption of oncogenic protein translation, tumor differentiation, and profound survival gains in the TH-MYCN mouse model. Specifically, an arginine/proline-free diet decreases the polyamine precursor ornithine and augments tumor polyamine depletion by difluoromethylornithine. This polyamine depletion causes ribosome stalling, unexpectedly specifically at adenosine-ending codons. Such codons are selectively enriched in cell cycle genes and low in neuronal differentiation genes. Thus, impaired translation of these codons, induced by the diet-drug combination, favors a pro-differentiation proteome. These results suggest that the genes of specific cellular programs have evolved hallmark codon usage preferences that enable coherent translational rewiring in response to metabolic stresses, and that this process can be targeted to activate differentiation of pediatric cancers.
Bio:
Raphael J. Morscher is a pediatric oncologist and principal investigator at the University of Zurich. His main research interests are in understanding personalized metabolic programs in pediatric cancers and fundamental principles in metabolic regulation of translation. Raphael grew up in Austria and received his MD and PhD from the Paracelsus Medical University in Salzburg. During his PhD he studied reprogramming of metabolism neuroblastoma with Barbara Kofler. In 2016 he moved to Princeton for a postdoctoral fellowship with Joshua Rabinowitz to develop in vivo stable isotope tracing approaches for the study of metabolic operation in health and disease. It was also at that time his work on folate-dependent tRNA modifications sparked interest to better understand how metabolism regulates protein translation at the tRNA /mRNA intersection. In 2022 Raphael established his own research group passionate about spanning from fundamental principles in metabolism to applications in the human system. When not studying metabolism, Raphael is often found on his bike or outside enjoying nature with his family.
Zoom link for attending remotely, if needed: https://epfl.zoom.us/j/68708003718
Practical information
- Informed public
- Free
Organizer
- Prof. Kristina Schoonjans, & Prof. Bart Deplancke, School of Life Sciences, EPFL
Contact
- Institute of Bioengineering (IBI), Dietrich REINHARD