Work

Tmic-05. Unveiling the Impact of Ptn-ptprz1 Signaling on Glioblastoma Progression Through Tumor Microenvironment Communication

Year: 2023

Type: article

Abstract: Glioblastoma (GBM) is the most lethal primary brain tumor with high rate of recurrence. GBM’s high inter- and intra-heterogeneity present a huge challenge to both disease modeling and treatment. Recent progress in the field has highlighted the role of signals associated with the microenvironment factor in driving tumor progression, suggesting that more detailed characterizations of the GBM microenvironment may provide novel therapeutic targets. In this study, we used a novel stem cell derived cortical organoid transplantation model, where we transplanted patient IDH wild type GBM cells onto organoids and provided multiple culture conditions to explore the impact of the environment on tumor cell identity. After several weeks of culture, single cell RNA-sequencing of tumor and non-neoplastic organoid cells was used to profile molecular features, demonstrating not only cellular composition of GBM and its surrounding normal brain cell, but also the bidirectional communication between the two. We observed functional heterogeneity where individual tumors responded differently to environmental perturbations. However, the most significant cell-cell interaction between tumors and the microenvironment was found to be PTN-PTPRZ1, which is well-maintained across all transplantation models we tested, as well as in re-analysis of published patient data that included tumor and normal cells. Encouraged by our previous works as well as others, which have revealed PTPRZ1 as an outer radial glia marker gene driving tumor invasion, we further verified PTN/PTPRZ1 expression not only in our organoid transplantation models but also on FFPE sections from GBM patients and mouse xenograft samples. These data suggest that this signaling axis promotes tumor progression through tumor – microenvironmental crosstalk, and using the organoid model we show a functional role for this communication. Together, this study presents a GBM organoid transplantation modeling system, which we leverage to detect a promising therapeutically target existing between GBM and its microenvironment.

Source: Neuro-Oncology

DOI: 10.1093/neuonc/noad179.1071