Spatiotemporal modeling reveals high-resolution invasion states in glioblastoma

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dc.contributor.authorManoharan, Varsha T.
dc.contributor.authorAbdelkareem, Aly
dc.contributor.authorGill, Gurveer
dc.contributor.authorBrown, Samuel
dc.contributor.authorGillmor, Aaron
dc.contributor.authorHall, Courtney
dc.contributor.authorSeo, Heewon
dc.contributor.authorNarta, Kiran
dc.contributor.authorGrewal, Sean
dc.contributor.authorDang, Ngoc H.
dc.contributor.authorAhn, Bo Y.
dc.contributor.authorOsz, Kata
dc.contributor.authorLun, Xueqing
dc.contributor.authorMah, Laura
dc.contributor.authorZemp, Franz
dc.contributor.authorMahoney, Douglas
dc.contributor.authorSenger, Donna L.
dc.contributor.authorChan, Jennifer A.
dc.contributor.authorMorrissy, A. S.
dc.date.accessioned2024-10-13T00:03:22Z
dc.date.available2024-10-13T00:03:22Z
dc.date.issued2024-10-10
dc.date.updated2024-10-13T00:03:22Z
dc.description.abstractAbstract Background Diffuse invasion of glioblastoma cells through normal brain tissue is a key contributor to tumor aggressiveness, resistance to conventional therapies, and dismal prognosis in patients. A deeper understanding of how components of the tumor microenvironment (TME) contribute to overall tumor organization and to programs of invasion may reveal opportunities for improved therapeutic strategies. Results Towards this goal, we apply a novel computational workflow to a spatiotemporally profiled GBM xenograft cohort, leveraging the ability to distinguish human tumor from mouse TME to overcome previous limitations in the analysis of diffuse invasion. Our analytic approach, based on unsupervised deconvolution, performs reference-free discovery of cell types and cell activities within the complete GBM ecosystem. We present a comprehensive catalogue of 15 tumor cell programs set within the spatiotemporal context of 90 mouse brain and TME cell types, cell activities, and anatomic structures. Distinct tumor programs related to invasion align with routes of perivascular, white matter, and parenchymal invasion. Furthermore, sub-modules of genes serving as program network hubs are highly prognostic in GBM patients. Conclusion The compendium of programs presented here provides a basis for rational targeting of tumor and/or TME components. We anticipate that our approach will facilitate an ecosystem-level understanding of the immediate and long-term consequences of such perturbations, including the identification of compensatory programs that will inform improved combinatorial therapies.
dc.identifier.citationGenome Biology. 2024 Oct 10;25(1):264
dc.identifier.urihttps://doi.org/10.1186/s13059-024-03407-3
dc.identifier.urihttps://hdl.handle.net/1880/119969
dc.language.rfc3066en
dc.rights.holderThe Author(s)
dc.titleSpatiotemporal modeling reveals high-resolution invasion states in glioblastoma
dc.typeJournal Article
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