Spatially Guided Multi-omic Analysis of Brain Tumors

Abstract

Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor, with no curative treatment options. Multiple studies have characterized at single cell resolution the GBM as being composed of transcriptional cell states interconnected with components in the tumor immune microenvironment (TME). The speaker’s group proposed and validated the first single cell guided functional classification of GBM in four tumor-intrinsic cell states which informed clinical outcome and delivered therapeutic options. However, single cell technologies are unable to unravel the spatial relationships among the cell states of GBM and between GBM cell states and TME. Spatially resolved transcriptomic technologies are emerging as powerful tools to reconstruct the spatial architecture of a tissue. The speaker’s group performed spatial transcriptomics of multicellular regions of interest (ROI) in 6 primary IDH wild-type GBM and 2 recurrent GBM with both CosMx Spatial Molecular Imager, which analyzes 1,000 RNA probes and 64 proteins at single cell resolution, and GeoMx Digital Spatial Profiler which profiles the whole transcriptome (~18,000 genes) at ROI resolution. The development of computational tools aimed to integrate spatial proximity and CosMx derived single-cell transcriptomics revealed spatial segregation of the tumor cell clones and cellular states and highlighted recurrent patterns of cell states, distinct TME cell types associated with coherent histopathological features across multiple samples. 

As the evolutionary trajectory of glioblastoma (GBM) is a multifaceted biological process that extends beyond genetic alterations alone, the speaker’s group performed an integrative proteogenomic analysis of 123 longitudinal glioblastoma pairs and identify a highly proliferative cellular state at diagnosis and replacement by activation of neuronal transition and synaptogenic pathways in recurrent tumors. Proteomic and phosphoproteomic analyses reveal that the molecular transition to neuronal state at recurrence is marked by post-translational activation of the wingless-related integration site (WNT)/ planar cell polarity (PCP) signaling pathway and BRAF protein kinase. Consistently, multi-omic analysis of patient-derived xenograft (PDX) models mirror similar patterns of evolutionary trajectory. Inhibition of B-raf proto-oncogene (BRAF) kinase impairs both neuronal transition and migration capability of recurrent tumor cells, phenotypic hallmarks of post-therapy progression. Combinatorial treatment of temozolomide (TMZ) with BRAF inhibitor, vemurafenib, significantly extends the survival of PDX models. The development of a spatial informed intercellular communication algorithm and the reconstruction of ligand-receptor-target networks will allow the discovery of tumor cell states-TME cross-talks and the biological signaling regulated by these interactions that are driving the heterogeneity of GBM and therefore potentially therapeutically targetable. Analysis of matched regions of interest profiled by GeoMx and spatial proteomics with CosMx further cross-validated the spatial ecosystem of glioblastoma as reconstructed at single-cell resolution. The group studies established a scalable approach to resolve the transcriptional heterogeneity of GBM and reconstruct the architecture of GBM cell states and tumor microenvironment.

About the Speaker

Prof. Antonio IAVARONE is a professor in the Department of Neurological Surgery at the University of Miami. He is also the Deputy Director of the Sylvester Comprehensive Cancer Center.

Prof. Iavarone seeks to unravel the biologic and genetic alterations driving subgroups of malignant brain tumors and exploit this information for rational therapeutic stratification. His team identified master regulators of cancer initiation and progression in distinct sub-groups of brain tumors. They discovered the first example of oncogenic and tumor addicting gene fusions in glioblastoma (FGFR3-TACC3) and reported that FGFR3-TACC3 fusions trigger tumorigenesis through activation of oxidative phosphorylation. These fusions are among the most frequent chromosomal translocations across all types of human cancer and the U.S. Food and Drug Administration (FDA) approved the targeting of these chromosomal translocations with FGFR inhibitors.

Prof. Iavarone chaired the Pan-Glioma ATLAS-TCGA Working Group and the Neurofibromatosis 1 synodos that united international researchers to formulate guidelines for accurate diagnosis and prognosis of glioma patients. By using all the computational and experimental tools at disposal, they combine innovations in both areas to continue making transformative mechanistic discoveries and provide personalized therapeutics to increasing number of patients with deadly tumor types.

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