SUMMARY Malignant astrocytomas are infiltrative and incurable brain tumors. Despite profound therapeutic implications, the identity of the cell(s) of origin has not been rigorously determined. We previously reported mouse models based on conditional inactivation of human astrocytoma-relevant tumor suppressors p53, Nf1, and Pten, wherein through somatic loss of heterozygosity, mutant mice develop tumors with 100% penetrance. In the present study, we show that tumor suppressor inactivation in neural stem/progenitor cells is both necessary and sufficient to induce astrocytoma formation. We demonstrate in vivo that transformed cells and their progeny undergo infiltration and multi-lineage differentiation during tumorigenesis. Tumor suppressor heterozygous neural stem/progenitor cultures from pre-symptomatic mice show aberrant growth advantage and altered differentiation, thus identifying a pre-tumorigenic cell population. Significance Identification of the original cell that gives rise to a tumor and whether it is a limited cell type has crucial implications for understanding cancer development. This knowledge is also requisite for rigorous investigation of tumor initiation mechanisms. Using fully penetrant mouse models, we identify neural stem/progenitor cells as cancer-initiating cells and derive insight into the behavior of these tumors. We also report malignant astrocytoma mouse models wherein tumor suppressor inactivation at embryonic, early postnatal, or adult ages induces tumor formation, and demonstrates the capacity of tumor cells to differentiate within the tumor. Our studies on pre-symptomatic mutant progenitor cultures indicate that the disease could be disseminating and acquire growth advantage long before the onset of clinical manifestations.

We previously reported that central nervous system (CNS) inactivation of Nf1 and p53 tumor suppressor genes in mice results in the development of low-grade to high-grade progressive astrocytomas. When the tumors achieve high grade, they are frequently accompanied by Akt activation, reminiscent of the frequent association of PTEN mutations in human high-grade glioma. In the present study, we introduced CNS heterozygosity of Pten into the Nf1/p53 astrocytoma model. Resulting mice had accelerated morbidity, shortened survival, and full penetrance of high-grade astrocytomas. Haploinsufficiency of Pten accelerated formation of grade 3 astrocytomas, whereas loss of Pten heterozygosity and Akt activation coincided with progression into grade 4 tumors. These data suggest that successive loss of each Pten allele may contribute to de novo formation of high-grade astrocytoma and progression into glioblastoma, respectively, thus providing insight into the etiology of primary glioblastoma. The presence of ectopically migrating neural stem/progenitor lineage cells in presymptomatic Pten-deficient mutant brains supports the notion that these tumors may arise from stem/progenitor cells. [Cancer Res 2008;68(9):3286-94]

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.

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Highlights d Tumor suppressor loss in NSCs and OLCs generate distinct murine GBM subtypes d Human GBM subtypes identified based on speciesconserved transcriptional profiles d Mouse and human cell lineage subtypes exhibit distinct tumor properties d OLC-associated GBMs show ERBB3 dependence and unique therapeutic sensitivity