MBRS-05. A p53 INDEPENDENT MOUSE MODEL OF GROUP 3 MEDULLOBLASTOMA

Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma

“…It has been demonstrated that MYC overexpression in astrocyte precursors is able to induce neoplastic formation, phenocopying Group 3 MB in mice. RNA-sequencing analyses of MYC-driven Group 3 mouse models revealed an upregulation of pro-glycolytic MYC-targets such as LDHA, PKM2, HK2 and Pyruvate dehydrogenase kinase 1 (PDK1) compared to normal cerebellum or SHH MB (Tao et al, 2019). This evidence supports the idea that MYC is a prominent positive regulator of the Warburg effect in MB.…”

“…A more promising therapeutic avenue encompasses the possibility of targeting pathways that are activated downstream of this oncoprotein; in this regard, MYCdependent metabolic adaptation is a very attractive phenomenon with several potential novel targets for MB (Figure 2). As it occurs in other cancers, MYC stimulates the Warburg effect in MB by directly trans-activating the expression of key glycolytic genes (Tao et al, 2019). Several crucial metabolism-related genes are bona fide MYC targets both in healthy and in transformed cells.…”

“…As soon as glucose enter the cells, hexokinase converts glucose into glucose-6-phosphate (G6P) which is consumed by multiple pathways such as glycolysis, OXPHOS, PPP, hexosamine biosynthetic pathway (HBP) or amino acid biosynthesis. By using (18F)fluorodeoxyglucose positron emission tomography (PET), a glycolytic metabolic phenotype has been reported in MB patients (Gururangan et al, 2004), and key genes involved in glycolysis are found to be significantly overexpressed in MYCdriven MB mouse models compared to SHH MB or nonneoplastic cerebellar tissue (Tao et al, 2019). Furthermore, both SHH MB and proliferating cells of the postnatal brain (i.e., hippocampus, subventricular zone, cerebellar external granule layer) preferentially express the glycolytic enzymes Hexokinase 2 (HK2) and the M2 isoform of pyruvate kinase (PKM2) (Gershon et al, 2013a(Gershon et al, , 2013bDi Magno et al, 2014;Tech et al, 2017).…”