Abstract
Intratumoral genetic heterogeneity is a widely accepted characteristic of human cancer, including the most common primary malignant brain tumor, glioblastoma. However, the variability in biological behaviors amongst cells within individual tumors is not well described. Invasion into unaffected brain parenchyma is one such behavior, and a leading mechanism of tumor recurrence unaddressed by the current therapeutic armamentarium. Further, providing insight into variability of tumor cell migration within individual tumors may inform discovery of novel anti-invasive therapeutics. In this study, ex vivo organotypic slice cultures from EGFR-wild type and EGFR-amplified patient tumors were treated with the EGFR inhibitor gefitinib to evaluate potential sub-population restricted intratumoral drug-specific responses. High-resolution time-lapse microscopy and quantitative path tracking demonstrated migration of individual cells are punctuated by intermittent bursts of movement. Elevation of population aggregate mean speeds were driven by subpopulations of cells exhibiting frequent high-amplitude bursts, enriched within EGFR-amplified tumors. Treatment with gefitinib specifically targeted high-burst cell subpopulations only in EGFR-amplified tumors, decreasing bursting frequency and amplitude. We provide evidence of intratumoral subpopulations of cells with enhanced migratory behavior in human glioblastoma, selectively targeted via EGFR inhibition. These data justify use of direct human tumor slice cultures to investigate patient-specific therapies designed to limit tumor invasion.
Highlights
The innate ability of glioblastoma to infiltrate normal brain is a clinical challenge, which limits efficacy of surgical resection, radiotherapy, and chemobiotherapies
Amplification at this locus, which is detected in 40–50% of GBM tissues[8], is typically mosaic and believed to enhance pro-invasive signaling through EGFR. Clinical imaging suggests this subset of receptor-amplified cells is enriched at the infiltrative tumor edge[9,10]. Supporting these data, our ex vivo slice cultures demonstrated increased tumor cell migration in EGFR-amplified tumors, and blockade of EGFR signaling with the small molecule inhibitor, gefitinib, induced a statistically significant reduction in migratory behavior within the same sample set[11]
While cellto-cell variation in gene expression and receptor tyrosine kinase amplification within GBM are well recognized, it remains unclear how genetically and epigenetically distinct subpopulations contribute to variation in cell behavior
Summary
The innate ability of glioblastoma to infiltrate normal brain is a clinical challenge, which limits efficacy of surgical resection, radiotherapy, and chemobiotherapies. Clinical imaging suggests this subset of receptor-amplified cells is enriched at the infiltrative tumor edge[9,10] Supporting these data, our ex vivo slice cultures demonstrated increased tumor cell migration in EGFR-amplified tumors, and blockade of EGFR signaling with the small molecule inhibitor, gefitinib, induced a statistically significant reduction in migratory behavior within the same sample set[11]. Despite evidence supporting the pro-migratory role of EGFR in GBM progression, trials of gefitinib and other targeted receptor tyrosine kinase (RTK) therapies, alone or in combination, failed to extend patient survival[12] This disconnect between in vitro drug studies and in vivo efficacy led the field to consider the prevalence of molecular heterogeneity within individual tumors as a mechanism of treatment resistance. Whether molecularly distinct subpopulations arise early in disease progression, or from treatment-resistant cells, their presence necessitates consideration in predicting response to, and failure of, targeted therapeutics
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