Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics

Abstract

Glioblastoma (GB) is the most common and aggressive primary brain malignancy, with poor prognosis and a lack of effective therapeutic options. Accumulating evidence suggests that intratumor heterogeneity likely is the key to understanding treatment failure. However, the extent of intratumor heterogeneity as a result of tumor evolution is still poorly understood. To address this, we developed a unique surgical multisampling scheme to collect spatially distinct tumor fragments from 11 GB patients. We present an integrated genomic analysis that uncovers extensive intratumor heterogeneity, with most patients displaying different GB subtypes within the same tumor. Moreover, we reconstructed the phylogeny of the fragments for each patient, identifying copy number alterations in EGFR and CDKN2A/B/p14ARF as early events, and aberrations in PDGFRA and PTEN as later events during cancer progression. We also characterized the clonal organization of each tumor fragment at the singlemolecule level, detecting multiple coexisting cell lineages. Our results reveal the genome-wide architecture of intratumor variability in GB across multiple spatial scales and patient-specific patterns of cancer evolution, with consequences for treatment design.tumor progression | high grade glioma

Multi-omics analysis of primary glioblastoma cell lines shows recapitulation of pivotal molecular features of parental tumors

“…In addition, these differences can be attributed to intratumoral subtype heterogeneity. 29,30 Tumors are distinct from PDCLs and usually cluster in 2 different groups. After exclusion of the differentially expressed genes, tumors clustered closely to their paired PDCLs.…”

“…However, there are some discrepancies between tumors and PDCLs which might represent real biological differences. We hypothesized several reasons for the discrepancies: (i) tumor heterogeneity which is well established for many tumors 31 and specifically for GBM, 29 (ii) different selective pressures during PDCL culturing in vitro compared with the tumor biological environment, and (iii) the microenvironment (ie, absence of immune cells) of PDCL culture conditions differ markedly from that of their paired parental tumors. 21 Although the molecular analysis was comprehensive and included several omics modalities, the sample size is relatively small and hence a larger set of paired parental tumors-PDCLs would be necessary to confirm our findings and to provide additional insights.…”

Molecular subtypes and differentiation programmes of glioma stem cells as determinants of extracellular vesicle profiles and endothelial cell‐stimulating activities

“…Molecularly, GBMs converge on a handful of distinct molecular groupings, of which The Cancer Genome Atlas (TCGA) identified four gene expression subtypes designated as: proneural (PN), neural (NEU), classical (CL) and mesenchymal (MES), which are regarded as biologically different diseases [5]. Superimposed on this complexity is also the evidence for intra-tumoural diversity of GBM cells [6], their rapid genetic evolution [7] and a frequently observed shift of PN GBM towards MES-like phenotype in the course of therapy [8]. …”

Phenotypic changes of acid-adapted cancer cells push them toward aggressiveness in their evolution in the tumor microenvironment

“…Most clinical cancer cells evolve and exist in a hostile microenvironment, characterized by acidosis, hypoxia, oxygen radicals (ROS) and nutrient deprivation. 2,3 It has been known that this environment induces genomic instability and selects for emergence of aggressive clones (clades) of cells, leading to genomic diversity, evident in intratumoral genetic heterogeneity, [4][5][6][7] which is a proximal cause of malignance and resistance. 8 Using dorsal window chambers, we have demonstrated that acidic environments promote tumor invasion and growth by degrading adjacent extracellular matrix].…”