Adult Lineage-Restricted CNS Progenitors Specify Distinct Glioblastoma Subtypes

Abstract

Summary A central question in glioblastoma multiforme (GBM) research is the identity of the tumor-initiating cell, and its contribution to the malignant phenotype and genomic state. We examine the potential of adult lineage restricted progenitors to induce fully penetrant GBM using central nervous system (CNS) progenitor-specific inducible Cre mice to mutate Nf1, Trp53 and Pten. We identify two phenotypically and molecularly distinct GBM subtypes governed by identical driver mutations. We demonstrate that the two subtypes arise from functionally independent pools of adult CNS progenitors. Despite histologic identity as GBM, these tumor types are separable based on the lineage of the tumor-initiating cell. These studies point to the cell of origin as a major determinant of GBM subtype diversity.

Lineage-Restricted OLIG2-RTK Signaling Governs the Molecular Subtype of Glioma Stem-like Cells

“…While these two molecular subtypes appear similar on a histopathological level, their expression profiles suggest that they might have disparate cellular origins. Recent elegant mouse modeling studies (Alcantara Llaguno et al, 2015) suggests that both multipotent neural stem cells (NSCs) and lineage-restricted oligodendrocyte precursor cells (OPCs) are capable of giving rise to anatomically and molecularly unique types of GBM when transformed with identical mutations (i.e., Tp53 , Pten , Nf1 deletion) using cell specific Cre-drivers ( Nestin creER for NSCs, Ascl1 creER for NSC/OPCs, Cspg4 creER for OPCs). These authors observed expression of Olig2 in both Type I (‘NSC’-like) and Type II (‘OPC-like’) tumors in their genetically engineered mouse models.…”

“…Intratumoral heterogeneity, diffuse infiltration throughout the brain parenchyma, and resistance to traditional therapies pose a major clinical challenge, which inevitably leads to tumor recurrence and the demise of the patient (Cloughesy et al, 2014). Recent work has highlighted the epigenetic and transcriptional networks of GSCs in human GBM (Suva et al, 2014), and their resemblance to niche-restricted progenitors of the adult mammalian brain (Alcantara Llaguno et al, 2015). Due to their unique ability to self-renew and differentiate into the neuro-glial lineages of the central nervous system (CNS), GSCs present a therapeutic burden by sustaining intratumoral heterogeneity and resistance to traditional therapies (Lathia et al, 2015).…”

An Hdac1/Rpd3-Poised Circuit Balances Continual Self-Renewal and Rapid Restriction of Developmental Potential during Asymmetric Stem Cell Division

“…To amplify the output of each division, stem cells generate intermediate progenitors that possess restricted developmental potential, and produce exclusively differentiated cell types (Paridaen and Huttner, 2014). If their developmental potential is not stably restrained, intermediate progenitors may become susceptible to oncogenic transformation (Alcantara Llaguno et al, 2015; Chen et al, 2010). Thus, the mechanisms that restrict the developmental potential of intermediate progenitors must be executed in an extremely efficient and robust manner to ensure normal development and tissue homeostasis.…”

New Advances and Challenges of Targeting Cancer Stem Cells

“…His work explored the stem cell origin of CSCs in malignant glioma and utilized the CDG transgene in specific promoter elements to target both CSCs and transit-amplifying cells. This discovery implicates that same genetic drivers in different cells of origin develop distinct glioblastoma multiforme (GBM) tumor types (6). …”

“…Furthermore, high-throughput screenings may help better determine the best personalized approach to treat patients. In addition, examining genomic alterations at premalignant stages (6, 7) could identity malignancy-specific targets.…”