胶质母细胞瘤细胞通过正常脑组织的弥漫性侵袭是肿瘤侵袭性、对常规疗法产生耐药性和患者预后不良的关键因素。更深入地了解肿瘤微环境 (TME) 的组成部分如何对整体肿瘤组织和侵袭程序做出贡献，可能会揭示改进治疗策略的机会。为了实现这一目标，我们将一种新颖的计算工作流程应用于时空分析的 GBM 异种移植队列，利用区分人类肿瘤和小鼠 TME 的能力，克服了以前在弥漫性侵袭分析中的局限性。我们的分析方法基于无监督反卷积，在整个 GBM 生态系统中对细胞类型和细胞活动进行无参考发现。我们提供了 15 个肿瘤细胞程序的综合目录，这些程序设置在 90 种小鼠大脑和 TME 细胞类型、细胞活动和解剖结构的时空背景下。与侵袭相关的不同肿瘤程序与血管周围、白质和实质侵袭的途径一致。此外，作为程序网络枢纽的基因子模块在 GBM 患者中具有高度预后作用。此处介绍的程序概要为肿瘤和/或 TME 成分的合理靶向提供了基础。我们预计我们的方法将促进生态系统层面对此类扰动的直接和长期后果的理解，包括确定补偿计划，为改进的组合疗法提供信息。© 2024。作者。

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.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.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.© 2024. The Author(s).