Progenitor-like Traits Contribute to Patient Survival and Prognosis in Oligodendroglial Tumors

Abstract

Purpose: Patient-derived glioma-propagating cells (GPC) contain karyotypic and gene expression profiles that are found in the primary tumor. However, their clinical relevance is unclear. We ask whether GPCs contribute to disease progression and survival outcome in patients with glioma by analyzing gene expression profiles. Experimental Design: We tapped into public sources of GPC gene expression data and derived a gene signature distinguishing oligodendroglial from glioblastoma multiforme (GBM) GPCs. By adapting a method in glioma biology, the Connectivity Map, we interrogated its strength of association in public clinical databases. We validated the top-ranking signaling pathways Wnt, Notch, and TGFβ, in GPCs and primary tumor specimens. Results: We observed that patients with better prognosis correlated with oligodendroglial GPC features and lower tumor grade, and this was independent of the current clinical indicator, 1p/19q status. Patients with better prognosis had proneural tumors whereas the poorly surviving cohort had mesenchymal tumors. In addition, oligodendroglial GPCs were more sensitive to Wnt and Notch inhibition whereas GBM GPCs responded to TGFβR1 inhibition. Conclusions: We provide evidence that GPCs are clinically relevant. In addition, the more favorable prognosis of oligodendroglial tumors over GBM could be recapitulated transcriptomically at the GPC level, underscoring the relevance of this cellular model. Our gene signature detects molecular heterogeneity in oligodendroglial tumors that cannot be accounted for by the 1p/19q status alone, indicating that stem-like traits contribute to clinical status. Collectively, these data highlight the limitation of morphology-based histologic analyses in tumor classification, consequently impacting on treatment decisions. Clin Cancer Res; 18(15); 4122–35. ©2012 AACR.

Mechanical confinement triggers glioma linear migration dependent on formin FHOD3

“…For this purpose, we used a glioma-propagating cell line isolated from a glioblastoma patient showing highly invasive glioblastoma ( Chong et al. , 2009 , 2015 ; Ng et al. , 2012 ).…”

A STAT3-based gene signature stratifies glioma patients for targeted therapy

“…GBM tumor specimens from the National Neuroscience Institute (NNI) were obtained with informed consent and de-identified in accordance with the SingHealth Centralised Institutional Review Board A, and GPC culture methods are described below 37–39,53 . All experiments were conducted with low-passage GPCs for which we previously demonstrated maintenance of phenotypic, transcriptomic, and karyotypic features similar to the primary tumor 53 .…”

“…Dose–response curves and cell viability were assessed using alamarBlue® cell viability assay (Serotec, Oxford, UK) 5 and 10 days post-treatment, respectively 37–39,53 . Dose–response curves for each cell line were generated from a mean of triplicate experiments using GraphPad Prism (GraphPad Software, Inc; USA) and IC 50 values were computed from 10-point titration curves ranging from 10 −4 to 10 2 μM.…”

Molecular Biomarkers of Cancer Stem/Progenitor Cells Associated with Progression, Metastases, and Treatment Resistance of Aggressive Cancers

“…The most cancers are heterogeneous diseases and include some biological subtypes characterized by specific genetic and/or epigenetic alterations occurring in cancer stem/progenitor cells and their differentiated progenies during cancer initiation and progression to locally invasive and metastatic stages (4, 6, 7, 44, 60, 78, 80, 95-109). Although the molecular events that govern the spread of cancer stem/progenitor cells and their differentiated progenies at preferential metastatic sites remain not precisely defined, some lines of evidence suggest that particular gene signatures of cancer cells at primary cancers may be associated with their propensity at metastasizing at specific tissues and organs (4, 6, 7, 95-102).…”

“…Although the molecular events that govern the spread of cancer stem/progenitor cells and their differentiated progenies at preferential metastatic sites remain not precisely defined, some lines of evidence suggest that particular gene signatures of cancer cells at primary cancers may be associated with their propensity at metastasizing at specific tissues and organs (4, 6, 7, 95-102). More particularly, the alterations in the gene products involved in the acquisition of aggressive and migratory properties by highly tumorigenic cancer stem/progenitor cells during the EMT program at the primary tumor may result in their invasion to near lymph nodes and tissues, dissemination through the peripheral circulation, and metastases at distant sites (Fig.…”