Modeling Cancer with Pluripotent Stem Cells

Gingold, Julian A.; Zhou, Ruoji; Lemischka, Ihor R.; Lee, Dung‐Fang

doi:10.1016/j.trecan.2016.07.007

Cited by 31 publications

(24 citation statements)

References 97 publications

(81 reference statements)

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“…Both of these studies identified novel potential drugs for brain tumors. As applications of iPSC models to cancer increase, the technology will likely gain increasing importance in developing and guiding cancer treatment [198]. …”

Section: Translating Lfs Ipsc Models Into Clinical Therapiesmentioning

confidence: 99%

Li–Fraumeni Syndrome Disease Model: A Platform to Develop Precision Cancer Therapy Targeting Oncogenic p53

Zhou

Gingold

et al. 2017

Trends in Pharmacological Sciences

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Li-Fraumeni syndrome (LFS) is a rare hereditary autosomal dominant cancer disorder. Germ-line mutations in TP53 are responsible for most cases of LFS. p53 is also the most commonly mutated gene in human cancers. Because inhibition of mutant p53 is considered a promising therapeutic strategy to treat these diseases, LFS provides a perfect genetic model to study p53 mutation-associated malignancies as well as screen potential compounds targeting oncogenic p53. In this review, we will briefly summarize the biology of LFS and the current understanding of oncogenic functions of mutant p53 in cancer development. We will discuss the strengths and limitations of current LFS disease models and touch on existing compounds targeting oncogenic p53 and in vitro clinical trials to develop new ones. Finally, we discuss how recently developed methodologies can be integrated into the LFS iPSC platform to develop precision cancer therapy.

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Section: Translating Lfs Ipsc Models Into Clinical Therapiesmentioning

confidence: 99%

Li–Fraumeni Syndrome Disease Model: A Platform to Develop Precision Cancer Therapy Targeting Oncogenic p53

Zhou

Gingold

et al. 2017

Trends in Pharmacological Sciences

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“…Still, the work of groups that have begun to apply iPSCs to phenocopy cancer, to explore pathological mechanisms, and to screen potential therapeutic compounds [126] highlights the potential of using human PSCs in medical research. These models of cancer pathogenesis overcome previous limitations related to patient sample availability or inapplicability of results from animal models or cell lines with inappropriate genetic backgrounds due to species differences.…”

Section: Discussionmentioning

confidence: 99%

“…Although iPSCs have been used for several years to model diseases such as neurodegeneration, mental retardation, heart disease, and metabolism disorders [125], they have only recently been used for cancer research [126]. …”

Section: Figurementioning

confidence: 99%

Osteosarcoma: Molecular Pathogenesis and iPSC Modeling

Lin

Jewell

Gingold

et al. 2017

Trends in Molecular Medicine

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129

117

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Rare hereditary disorders provide unequivocal evidence of the importance of genes in human disease pathogenesis. Familial syndromes that predispose to osteosarcomagenesis are invaluable in understanding the underlying genetics of this malignancy. Recently, patient-derived pluripotent stem cells (iPSCs) have been successfully utilized to model Li-Fraumeni syndrome (LFS)-associated bone malignancy, demonstrating that iPSCs can serve as an in vitro disease model to elucidate osteosarcoma etiology. Here, we provide an overview of osteosarcoma predisposition syndromes and review recently established iPSC disease models for these familial syndromes. Merging molecular information gathered from these models with the current knowledge of osteosarcoma biology will help us gain a deeper understanding of the pathological mechanisms underlying osteosarcomagenesis and potentially aid in the development of future patient therapies.

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“…Kinase inhibition is a primary therapeutic strategy and our finding that transcriptional heterogeneity is induced by constitutive kinase inhibition has profound implications for such therapies. Stem cells share parallel features with cancer cells 68 and current inhibitor therapies may have unintended consequences of driving both inter-and intra-tumour heterogeneity. Heterogeneity can drive tumour development across a broad spectrum of cancers, presenting opportunities for drug resistant subclones and metastatic potential to arise 69 .…”

Section: Discussionmentioning

confidence: 99%

Signalling pathways drive heterogeneity of ground state pluripotency

McEwen

Linnett

Leitch

et al. 2018

Preprint

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Pluripotent stem cells (PSCs) can self-renew indefinitely while maintaining the ability to generate all cell types of the body. This plasticity is proposed to require heterogeneity in gene expression, driving a metastable state which may allow flexible cell fate choices.Contrary to this, naive PSC grown in fully defined '2i' environmental conditions, containing small molecule inhibitors of MEK and GSK3 kinases, show homogenous pluripotency and lineage marker expression. However, here we show that 2i induces greater genome-wide heterogeneity than traditional serum-containing growth environments at the population level across both male and female PSCs. This heterogeneity is dynamic and reversible over time, consistent with a dynamic metastable equilibrium of the pluripotent state. We further show that the 2i environment causes increased heterogeneity in the calcium signalling pathway at both the population and single-cell level. Mechanistically, we identify loss of robustness regulators in the form of negative feedback to the upstream EGF receptor. Our findings advance the current understanding of the plastic nature of the pluripotent state and highlight the role of signalling pathways in the control of transcriptional heterogeneity. Furthermore, our results have critical implications for the current use of kinase inhibitors in the clinic, where inducing heterogeneity may increase the risk of cancer metastasis and drug resistance.RNAs, are not reduced and are instead increased in 2i ( Fig. 2i) arguing against this. This Animal studiesAnimal studies were authorized under a UK Home Office Project License and carried out in a Home Office-designated facility. Cell cultureESCs and EGCs (Oct4ΔPE-GFP) were derived and cultured as previously described 18 .Serum culture conditions contain 15% FCS, 0.1 mM MEM nonessential amino acids, 2 mM lglutamine, 1 mM sodium pyruvate, 0.1 mM 2-mercaptoethanol and 1000U/mL LIF in DMEM-F12 with maintenance on a mouse embryonic fibroblast (MEF) feeder layer. 2i culture conditions contain 1 μ M PD0325901, 3 μ M CHIR99021 and 1000U/mL LIF in N2B27 medium, maintained on laminin (10 μ g/ml). Cells were incubated at 5% CO 2 , 95% relative humidity. All samples were profiled at fewer than 23 passages. For time-course transcriptome profiling EGCs were derived and maintained in either serum or 2i and collected every 3 passages from 11-17. Population transcriptomicsSamples were prepared and processed as described previously. Briefly, 100ng RNA was fragmented, labelled and hybridized to Affymetrix GeneChip Mouse Gene 1.0 ST Arrays.Data was preprocessed in R using robust multiarray averaging, variance stabilising transformation and Combat batch correction 70 . Limma was used for differential expression analysis and for linear regression against cell subtypes, sex and passage 71 . Differential variance was tested using the studentised Breusch-Pagan test with culture condition as the independent variable. Testing statistical enrichment of gene sets was performed using functional annotation ontology 40 ...

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Modeling Cancer with Pluripotent Stem Cells

Cited by 31 publications

References 97 publications

Li–Fraumeni Syndrome Disease Model: A Platform to Develop Precision Cancer Therapy Targeting Oncogenic p53

Li–Fraumeni Syndrome Disease Model: A Platform to Develop Precision Cancer Therapy Targeting Oncogenic p53

Osteosarcoma: Molecular Pathogenesis and iPSC Modeling

Signalling pathways drive heterogeneity of ground state pluripotency

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