Elucidating the diversity of malignant mesenchymal states in glioblastoma by integrative analysis

Abstract

Background Multiple glioblastoma studies have described a mesenchymal (MES) state, with each study defining the MES program by distinct sets of genes and highlighting distinct functional associations, including both immune activation and suppression. These variable descriptions complicate our understanding of the MES state and its implications. Here, we hypothesize that there is a range of glioma MES states, possibly reflecting distinct prior states in which a MES program can be induced, and/or distinct mechanisms that induce the MES states in those cells. Methods We integrated multiple published single-cell and bulk RNA sequencing datasets and MES signatures to define a core MES program that recurs across studies, as well as multiple function-specific MES signatures that vary across MES cells. We then examined the co-occurrence of these signatures and their associations with genetic and microenvironmental features. Results Based on co-occurrence of MES signatures, we found three main variants of MES states: hypoxia-related (MES-Hyp), astrocyte-related (MES-Ast), and an intermediate state. Notably, the MES states are differentially associated with genetic and microenvironmental features. MES-Hyp is preferentially associated with NF1 deletion, overall macrophage abundance, a high macrophage/microglia ratio, and M2-related macrophages, consistent with previous studies that associated MES with immune suppression. In contrast, MES-Ast is associated with T cell abundance and cytotoxicity, consistent with immune activation through expression of MHC-I/II. Conclusions Diverse MES states occur in glioblastoma. These states share a subset of core genes but differ primarily in their association with hypoxia vs. astrocytic expression programs, and with immune suppression vs. activation, respectively.

Defining ancestry, heritability and plasticity of cellular phenotypes in somatic evolution

“…Notably, this inference suggests that, in this patient, the MES-like state derives from transitioning AC-like cells. This observation is consistent with recent findings that show that many MES-like cells have AC-like properties [Chanoch-Myers et al, 2022] and that the receptors (e.g., OSMR, EGFR, PDGFRB, and AXL) for ligands that drive transition into the MES-like state are expressed in AC-like cells but not stem-like cells [Hara et al, 2021]. PATH transition inferences from another human patientderived GBM sample MGH122, from , agreed with inferences from MGH115, revealing that of the neurodevelopmental-like cell states, AC-like cells appear to transition to the MES-like state at the highest rate (Fig.…”

Glioblastoma is spatially organized by neurodevelopmental programs and a glial-like wound healing response

“…In contrast, MES1 was associated with complement activation, plasma membrane repair, plasminogen activation, and coagulation, all of which are related to haemostasis, the extravascular clotting of extravasated blood or plasma. We further examined a recent integrated analysis of 12 published glioblastoma datasets, which had identified 27 core MES-like genes 28 , most of which have known functions related to wound healing ( Table S1 ). Notably, every single MES-core gene was robustly and significantly (FDR < 0.05, fold-change > 1.2) induced in a well-powered timecourse study of skin wound healing 29 ( Figure S1D ).…”

A non-randomized, open-label, dose-finding, first-in-human trial of combined cytotoxic and immune-stimulatory gene therapy for primary adult high-grade glioma: transgene expression persists up to 17 months post-vector injection

“…This might indicate a potential increased downregulation of T cell activity by macrophages/microglia, as recently described. 34, 35…”