Medulloblastoma is one of the most common and aggressive brain tumors in children and is characterized by its high invasiveness. Despite significant advantages in treatment, the resistance to chemotherapies remains an impediment to patient care. Recurrence of medulloblastoma is observed in 20-40% of cases several years after the initial diagnosis and is often associated with resistance to treatments. Our research group has generated and characterized a novel in vitro MB chemo-resistant cell lines (MB-R) model to tackle this challenge. Multiomic analysis of MB-R lines has revealed a dysregulated molecular phenotype, particularly in cellular metabolism, compared to their chemotherapy-sensitive counterparts. In this thesis, we demonstrated that redox homeostasis is a critical hallmark in medulloblastoma resistance, as the tight regulation of reactive oxygen species contributes to tumor cell survival. Indeed, MB-R cancer cells upregulate their antioxidant systems and maintain lower ROS levels to prevent oxidative damage. The Nrf2 signalling pathway is one of the most critical mechanisms employed by mammalian cells to resist oxidative stress and xenobiotic toxicity, and it was found to be upregulated in our MB-R model. Nrf2 enhances the production of NADPH and other cytoprotective enzymes, providing cells with the reducing power necessary to counteract oxidative stress. By replicating the protocol used to induce chemotherapy resistance acquisition in MB cells with Nrf2 knocked down, we demonstrated that Nrf2 plays a direct role in the development of chemotherapy resistance. In conclusion, as the Nrf2 pathway drives MB progression and chemoresistance, we proposed a pharmacological strategy to inhibit Nrf2 transcriptional activation in MB cells as a potential therapeutic strategy to improve the efficacy of chemotherapy and reduce the onset of resistance.
Medulloblastoma is one of the most common and aggressive brain tumors in children and is characterized by its high invasiveness. Despite significant advantages in treatment, the resistance to chemotherapies remains an impediment to patient care. Recurrence of medulloblastoma is observed in 20-40% of cases several years after the initial diagnosis and is often associated with resistance to treatments. Our research group has generated and characterized a novel in vitro MB chemo-resistant cell lines (MB-R) model to tackle this challenge. Multiomic analysis of MB-R lines has revealed a dysregulated molecular phenotype, particularly in cellular metabolism, compared to their chemotherapy-sensitive counterparts. In this thesis, we demonstrated that redox homeostasis is a critical hallmark in medulloblastoma resistance, as the tight regulation of reactive oxygen species contributes to tumor cell survival. Indeed, MB-R cancer cells upregulate their antioxidant systems and maintain lower ROS levels to prevent oxidative damage. The Nrf2 signalling pathway is one of the most critical mechanisms employed by mammalian cells to resist oxidative stress and xenobiotic toxicity, and it was found to be upregulated in our MB-R model. Nrf2 enhances the production of NADPH and other cytoprotective enzymes, providing cells with the reducing power necessary to counteract oxidative stress. By replicating the protocol used to induce chemotherapy resistance acquisition in MB cells with Nrf2 knocked down, we demonstrated that Nrf2 plays a direct role in the development of chemotherapy resistance. In conclusion, as the Nrf2 pathway drives MB progression and chemoresistance, we proposed a pharmacological strategy to inhibit Nrf2 transcriptional activation in MB cells as a potential therapeutic strategy to improve the efficacy of chemotherapy and reduce the onset of resistance.
Nrf2-driven metabolic reprogramming sustains chemotherapy resistance in Medulloblastoma.
ZANOLLI, ARIANNA
2023/2024
Abstract
Medulloblastoma is one of the most common and aggressive brain tumors in children and is characterized by its high invasiveness. Despite significant advantages in treatment, the resistance to chemotherapies remains an impediment to patient care. Recurrence of medulloblastoma is observed in 20-40% of cases several years after the initial diagnosis and is often associated with resistance to treatments. Our research group has generated and characterized a novel in vitro MB chemo-resistant cell lines (MB-R) model to tackle this challenge. Multiomic analysis of MB-R lines has revealed a dysregulated molecular phenotype, particularly in cellular metabolism, compared to their chemotherapy-sensitive counterparts. In this thesis, we demonstrated that redox homeostasis is a critical hallmark in medulloblastoma resistance, as the tight regulation of reactive oxygen species contributes to tumor cell survival. Indeed, MB-R cancer cells upregulate their antioxidant systems and maintain lower ROS levels to prevent oxidative damage. The Nrf2 signalling pathway is one of the most critical mechanisms employed by mammalian cells to resist oxidative stress and xenobiotic toxicity, and it was found to be upregulated in our MB-R model. Nrf2 enhances the production of NADPH and other cytoprotective enzymes, providing cells with the reducing power necessary to counteract oxidative stress. By replicating the protocol used to induce chemotherapy resistance acquisition in MB cells with Nrf2 knocked down, we demonstrated that Nrf2 plays a direct role in the development of chemotherapy resistance. In conclusion, as the Nrf2 pathway drives MB progression and chemoresistance, we proposed a pharmacological strategy to inhibit Nrf2 transcriptional activation in MB cells as a potential therapeutic strategy to improve the efficacy of chemotherapy and reduce the onset of resistance.File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.12608/80644