Vorschau

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Abstract

Tumors inherit characteristics from their tissue of origin, displaying varied molecular and functional features based on their specific progenitor cells. Leveraging this constraint to isolate similarities between healthy and tumor cells, I developed ptalign as a means to place tumor cells within a fixed healthy lineage trajectory, using healthy stem cell transitions as a template to infer a tumor pseudolineage in the absence of lineage tracing. This approach offers several unique benefits: it facilitates the transfer of vital contextual information from healthy references to clarify tumor processes and enables the comparison of pseudotime expression dynamics across multiple tumors to identify stage- or group-specific tumor vulnerabilities. This view of tumor organization through the lens of healthy lineage transitions provides valuable context for the development of targeted tumor interventions and personalized therapies.

In this thesis, I demonstrate this approach through a systematic study of glioblastoma pseudolineages based in the adult neural stem cell (NSC) lineage. Delineating glioblastoma hierarchies into Quiescence-, Activation-, and Differentiation-stage cells revealed the essential role of the Quiescence-Activation transition in determining patient outcomes. In healthy NSCs, Wnt signaling is a crucial regulator of this transition, and comparing pseudolineage expression dynamics at this transition identified the secreted Wnt antagonists SFRP1 and NOTUM as recurrently dysregulated in glioblastomas. Reintroducing SFRP1 stalled tumor progression, significantly increasing overall survival of tumor-bearing mice by rewiring tumor cell fate to an astrocytic pseudolineage. This SFRP1-induced remodeling was reversed with a small molecule inhibitor, asserting the lineage potential of tumor astrocytes and challenging prevailing assumptions about their plasticity. These findings position SFRP1 as a potent modulator of cell fate with promising therapeutic potential, highlighting the advantages of a comparative approach to studying tumor cells rooted in the similarities to their healthy counterparts.

Overall, ptalign pseudolineages provide a framework for viewing tumor organization through the lens of healthy lineage transitions, uncovering critical vulnerabilities that enable targeted interference in tumor hierarchies.