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Abstract

Recent technological strides in cancer research have unveiled the landscape of somatic mutations in propelling uncontrolled growth. However the intricate organization of cellular hierarchies governing and fueling progression remains uncharted. Adult neural stem cells are specialized astrocytes in the neurogenic niches of the brain, continually generating de novo lineages under strictly governed conditions, and capable of responding to injury. Viewing astrocytic origin of glioblastoma as a misappropriated regeneration attempt in the aging brain, adult neural stem cell lineage represents the ideal model to draw direct comparisons and contextualize malignant organization of neoplastic cells. In this dissertation, I demonstrate that glioblastoma cells - much like their healthy counterparts - establish a cellular hierarchy spanning quiescence, activation and differentiation stages, respectively. Enabled by the single cell workflows I established to quantify canonical Wnt-activity in health and disease, I found out that; unlike during normal neurogenesis, key Wnt pathway modulators are recurrently dysregulated during glioblastoma progression. Directly comparing healthy and cancerous trajectories in the adult mammalian brain, I identified SFRP1 - a secreted Wnt antagonist functioning as the gatekeeper of neurogenic activation of astrocytes - to be lost in glioblastomas. Re-introducing the expression of SFRP1 in a patient derived xenograft model robustly blocked tumor progression and significantly increased overall survival in mice. Single cell RNA sequencing validated by dual immunofluorescence-spatial transcriptomics revealed that SFRP1 overexpression induces a quiescent astrocyte-like phenotype that is concomitantly reflected at tumor’s methylome. Together, I present an innovative framework to re-interpret cellular structures in tumors informed by the tissue of origin trajectories, introducing the use of DNA methylation as a means to stratify patients and monitor disease evolution as well as discover actionable targets for precision medicine.