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Targetable programs of adult cancer are ontogenically rooted within early cell fate trajectories of human pluripotent state [array]

ABSTRACT: Recognized molecular similarities between pluripotency and cancer have recently been underscored with multi-omics campaigns revealing stemness networks that are shared between human pluripotent stem cells (hPSCs) and tumors, where tumors types cluster based on tissue origins. Informed by these in silico studies, we now demonstrate hPSCs serve as a source of networks that define properties of adult tissue oncogenesis. Single cell deconstruction of hPSCs allowed germ layer primed subsets to be identified that corresponded to lineage specified adult cancers. Chemical probes that induced germ layer differentiation of hPSCs also suppressed adult cancers, but were restricted to tumors of shared origin with germ layer specification. Metallothioneines induced mesoderm differentiation of hPSC with exclusive ability to overcome differentiation block of human leukemia. Our study provides causal evidence for a relationship between pluripotent state and human cancer that defines oncogenic reprogramming and thereby identify covert targets for cancer therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE133041 | GEO | 2023/05/17

REPOSITORIES: GEO

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Project description:Human pluripotent stem cells (hPSCs) tend to acquire genomic aberrations in culture, the most common of which is the trisomy of chromosome 12. Interestingly, trisomy 12 is also prevalent in germ cell tumors (GCTs). Here, we aimed to dissect the cellular and molecular implications of trisomy 12 in hPSCs. A genome-wide gene expression analysis revealed that trisomy 12 profoundly affects the global gene expression profile of hPSCs, inducing a transcriptional program very similar to that of CGTs. Direct comparison of the proliferation, replication, differentiation and apoptosis between diploid and aneuploid hPSCs revealed that trisomy 12 significantly increases the proliferation rate of hPSCs. Increased replication largely accounts for the increased proliferation observed, and may explain the selection advantage that trisomy 12 confers to hPSCs. A comparison of the tumors induced by diploid and aneuploid hPSCs further demonstrated that trisomy 12 increases the tumorigenicity of hPSCs, inducing transcriptionally-distinct teratomas, from which pluripotent cells can be recovered. Lastly, a chemical screen of 89 anticancer drugs against diploid and aneuploid hPSCs discovered that trisomy 12 raises the sensitivity of hPSCs to several replication inhibitors, suggesting that the increased proliferation and tumorigenicity of these aberrant cells also makes them more vulnerable, and might potentially be used for their selective elimination from culture. Together, our findings demonstrate the extensive effect of trisomy 12 on the gene expression signature and on the cellular behavior of hPSCs, and highlight the danger posed by this trisomy for the successful use of hPSCs in basic research and in regenerative medicine. Expression data from diploid and aneuoploid human pluripotent stem cells, teratomas derived from them, and pluripotent-like cells recovered from these teratomas total RNA was isolated from undifferentiated human pluripotent stem cells grown under standard human ES conditions, or from teratomas derived from them, or from ES-like cells recovered from these teratomas.

Project description:Embryogenesis is tightly regulated by multiple levels of epigenetic systems such as DNA methylation, histone modification, and chromatin remodeling. DNA methylation patterns are erased in primordial germ cells and in the interval immediately following fertilization. Subsequent reprogramming occurs by de novo methylation and demethylation. Variance of DNA methylation patterns between different cell types is not well understood. Here, using methylated DNA immunoprecipitation and tiling array technology, we have comprehensively analysed DNA methylation patterns at proximal promoter regions in mouse embryonic stem (ES) cells, ES cell-derived early germ layers (ectoderm, endoderm and mesoderm) and four adult tissues (brain, liver, skeletal muscle and sperm). Most of the methylated regions in the three germ layers and in the three adult somatic tissues are shared in common. This commonly methylated gene set is enriched in germ cell associated genes that are generally transcriptionally inactive in somatic cells. We also compared DNA methylation patterns with global mapping of histone H3 lysine 4/27 trimethylation, and found that gain of DNA methylation correlates with loss of histone H3 lysine 4 trimethylation. Taken together, our findings indicate that differentiation from ES cells to the three germ layers is accompanied by an increase in the number of commonly methylated DNA regions and that these tissue-specific alterations are present for only a small number of genes. Our findings indicate that DNA methylation at the proximal promoter regions of commonly methylated genes act as an irreversible mark which fixes somatic lineage by repressing transcription of germ cell specific genes. Using the MeDIP on chip protocol, we immunoprecipitated methylated DNA from R1 ES cell, SK7 cell, as well as SK7 derived-Ectoderm, - Endoderm, -Paraxial mesoderm, brain, liver, skeletal muscle, and sperm, and hybridized to a genome tiling array. The three germ layer lineages from ES cells were confirmed by the expression of specific marker genes in each germ layer (see related expression analysis).

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Targetable programs of adult cancer are ontogenically rooted within early cell fate trajectories of human pluripotent state [array]

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