STEM-07. THE ONGOING PROCESS TO IDENTIFY AND CHARACTERIZE THE DORMANT ANCESTRAL FOUNDER CSC IN IDH-WILDTYPE GLIOBLASTOMA, THE SINGLE AND CRUCIAL CELL TO TARGET TO OVERCOME BOTH CAUSES OF THERAPEUTIC RESISTANCE

Abstract It is now undoubtedly clear that IDH-wildtype glioblastoma ancestral founder CSC was born as a premalignant progenitor in the astrocytic ribbon layer of the SVZ. After acquiring the proper driver genomic events, it becomes the first founder CSC and, dividing symmetrically, will give rise to a population of founder CSCs with the ability to migrate and micro-infiltrate quiescently the entire supratentorial brain parenchyma. Importantly, this pre-growth micro-infiltration is the only one able to give rise to distant relapses. By collecting multiple spatially separate samples in the tumor, the phylogenetic tree of the primary tumor bulk can be reconstructed. However, innovative therapeutic solutions cannot be inferred by analyzing the tumor bulk (where the ancestral CSCs are invariably extinct) but instead in the micro-infiltrated brain, where the ancestral founder CSCs lie quiescently in the perivascular niches. The codified ethical methods to sample the perimarginal micro-infiltrated brain parenchyma are enabling our research group to isolate, characterize, and reproduce the dormant ancestral founder CSC. In the bulk, we can reconstruct the tumor phylogenetic tree and identify evolutionary driver and passenger events as well as the multitude of CSC variants. The ethical sampling of the perimarginal micro-infiltrated brain parenchyma is now allowing us to identify and characterize the ancestral founder CSCs (and markers of outer radial glia are typifying them), which hibernate in the perivascular parenchymal niches of the supratentorial brain (their activation being the only cause of distant recurrences). The first cause of therapeutic resistance is due to intratumor heterogeneity, while the second cause is the silent presence in the entire supratentorial brain of dormant ancestral founder CSCs from the pre-growth micro-infiltration. After finishing the process of identification and characterization of the dormant ancestral founder CSC, we’ll obtain the target that can overcome both causes of resistance and provide novel, effective therapeutic solutions soon.