Submission ID 92173
| Poster Code | HR-P-58 |
|---|---|
| Title of Abstract | Delineating and targeting a novel metabolism-based post-translational mechanism regulating the abundance of the 'undruggable' oncoprotein c-MYC in medulloblastoma |
| Abstract Submission | Brain tumors are the leading cause of cancer death in children, and medulloblastoma (MB) is the most common pediatric central nervous system malignancy. Amplification of the c-MYC oncogene is frequently observed in the most aggressive and lethal subgroup of this disease, group 3 (G3), but not in other subgroups. Patients that have G3 MB tumors with high c-MYC abundance are more likely to present as metastatic and are prone to develop fatal recurrent tumors. Unfortunately, the functional ubiquity and disordered structure of c-MYC makes it difficult to target for cancer treatment. Therefore, it is critical to identify novel, out-of-the-box strategies to suppress oncogenic c-MYC in highly aggressive G3 MB brain tumors. Recently, metabolism has emerged as a major regulator of overall cellular signaling processes through post-translational and epigenetic mechanisms. While c-MYC is known to regulate cellular metabolism, whether metabolism plays a role in reciprocally supporting enhanced c-MYC abundance in cancer is unknown. We hypothesize that an intrinsic feedback mechanism may exist where metabolic activity modulates c-MYC abundance that could be exploited as a therapeutic strategy to improve outcomes for G3 MB patients. Using various well-characterized G3 MB cells, orthotopic intracerebellar xenograft models, patient tumor bioinformatics analyses, and detailed biochemical characterization, we have identified a novel metabolism-dependent post-translational modification that regulates c-MYC stability in G3 MB. In-depth molecular analyses unveiled that c-MYC is susceptible to oxidation and proteasomal degradation under conditions of metabolic stress. Targeting mitochondrial respiration via inhibition of complex-I led to the accumulation of reactive oxygen species (ROS) and depletion of c-MYC abundance, which impaired the growth of intracerebellar G3 MB xenograft tumors in mice, significantly prolonging animal survival. Altogether, these findings unveil a novel mechanism through which metabolism regulates the post-translational stability of c-MYC and provides insights for designing rationale therapeutic strategies for the treatment of MB patients. |
| Please indicate who nominated you | Dr. Hope Anderson, Vice-Dean Graduate & Post Doctoral Studies, Rady Faculty of Health Sciences, University of Manitoba |
| What Canadian Institutes of Health Research (CIHR) institute is your research most closely aligned? | Cancer Research |
| What Canadian Institutes of Health Research (CIHR) pillar of health research does your research fall under? | Biomedical |
| PDF of abstract | ICAM-2023-Abstract_Emma-Martell.pdf 2023-01-30 at 12:37:29 |
| Presenter and Author(s) | Emma Martell Tamra Werbowetski-Ogilvie Versha Banerji Sheila Singh Tanveer Sharif Emma Martell Helgi Kuzmychova Esha Kaul Harshal Senthil Subir Chowhury Ludivine Morrison |
