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Single-cell bottlenecks and dead-ends during glioma premalignancy

ABSTRACT: Glial brain tumors are composed of diverse cell types whose origins are just beginning to be unraveled. The final cellular composition of a fulminant glioma could be very different from the regulatory adaptations needed, or attempted, to establish the tumor ecosystem from an originating mutant. Using a genetically engineered mouse model that combines inducible Nf1?Trp53 loss with lineage tracing, we measured bulk and subpopulation transcriptomes during early gliomagenesis in oligodendrocyte precursor cells (OPCs). Large populations or small pools of labeled OPCs were isolated directly from their niches by laser-capture microdissection and profiled by RNA sequencing. The bulk transcriptomes of frank gliomas had relatively little in common with age-matched OPCs, but we detected generic adaptations to tumor-suppressor loss shortly after induced Nf1?Trp53 deletion. The diversity of OPCs targeted for deletion was uncovered by a stochasticprofiling fluctuation analysis of 10-cell measurements that revealed a spectrum of stem-progenitor, proneural, and mesenchymal states. Months after Nf1?Trp53 deletion, bulk differences were difficult to detect reliably, as the 10-cell data indicated several mixed-lineage states, including those not previously documented in glioma that likely marked dead-end niches. In addition, we identified a group of mutant cells devoid of conventional lineage markers, which abundantly expressed key effectors of nonsense-mediated decay and homologydependent DNA repair. In Trp53-null OPCs driven to proliferate by Nf1 deletion, ?productive? (i.e., tumorigenic) niche formation and resolution of replication stress stand out as predicted bottlenecks for glioma initiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE147360 | GEO | 2021/01/05

REPOSITORIES: GEO

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Project description:Cancer results from molecular mutations occurring in specific cell types, thus determining the cell-of-origin is critical for effective cancer treatment. Inferring such information from terminal tumors can be misleading because malignant tumor cells tend to acquire aberrant properties. Animal models are widely used because one can initiate mutations in specific cell types. However, cell-of-mutation that harbors initial molecular changes may not directly transform, rather merely passes along mutations to its progeny cell lineage, which then serves as cell-of-origin and finally transforms into malignancy. Such a problem is exemplified in the glioma field: glioma can be induced either by mutating tumor suppressor genes in neural stem cells (NSCs) or by over-expressing oncogenes in restricted progenitor cells such as oligodendrocyte precursor cells (OPCs). However, for the NSC glioma model, it remains unknown whether NSCs directly transform or simply pass along mutations to OPC lineage for malignancy. Here we use a genetic system termed Mosaic Analysis with Double Markers (MADM) to study the earliest stage of gliomagenesis from mutated NSCs. At an in vivo single-cell resolution, we unbiasedly analyzed tumorigenic potential of NSCs and all cell lineages derived from them. At pathologically undetectable pre-transforming phases, we found no significant aberrant growth of mutant NSCs and their derivatives except for the OPC lineage. We then tracked the tumor progression from earliest stage and confirmed the expansion of OPCs lead to gliomagenesis. Consistently, transcriptome profiling reveals that terminal-stage tumor cells display salient OPC features and resemble human proneural subtype of glioblastoma multiform (GBM). Most importantly, introducing the same mutations directly into OPCs was sufficient for malignant transformation and these tumor cells are indistinguishable in their gene expression profiles from those in which the first mutations were introduced into NSCs. Our findings strongly implicate OPCs as the transforming cell type for glioma even when initial mutations could occur in NSCs, and highlight the importance of analyzing early phases of tumorigenesis to distinguish cell-of-origin from cell-of-mutation. 44K Mouse Development Oligo Microarrays from Agilent Technologies were used for microarray analysis. For each experiment, total RNA was fluorescently labeled and hybridized directly against a common reference sample generated from the RNA pool of four WT P17 mouse brain neocortex.

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Single-cell bottlenecks and dead-ends during glioma premalignancy

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