scholarly journals Cancer avatars derived from genetically engineered pluripotent stem cells allow for longitudinal assessment of tumor development

2019 ◽  
Author(s):  
Tomoyuki Koga ◽  
Isaac A. Chaim ◽  
Jorge A. Benitez ◽  
Sebastian Markmiller ◽  
Alison D. Parisian ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Cancer Biology ◽  
Tumor Heterogeneity ◽  
Tumor Development ◽  
Human Tumor ◽  
Genetically Engineered ◽  
Tumor Evolution ◽  
Longitudinal Assessment ◽  
Cellular Models

ABSTRACTMany current cellular models aimed at elucidating cancer biology do not recapitulate pathobiology including tumor heterogeneity, an inherent feature of cancer that underlies treatment resistance. Here we introduce a new cancer modeling paradigm using genetically engineered human pluripotent stem cells (hiPSCs) that capture authentic cancer pathobiology. Orthotopic engraftment of neural progenitor cells derived from hiPSCs that have been genome-edited to contain tumor-associated genetic driver mutations revealed by The Cancer Genome Atlas project for glioblastoma (GBM) result in formation of high-grade gliomas. As observed in GBM patient samples, these models harbor inter-tumor heterogeneity resembling different GBM molecular subtypes, and intra-tumor heterogeneity. Further, re-engraftment of primary tumor neurospheres generates secondary tumors with features characteristic of patient samples and present mutation-dependent patterns of tumor evolution. Thus, these cancer avatar models provide a platform for a comprehensive longitudinal assessment of human tumor development as governed by molecular subtype mutations and lineage-restricted differentiation.

scholarly journals Author Correction: Longitudinal assessment of tumor development using cancer avatars derived from genetically engineered pluripotent stem cells

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Tomoyuki Koga ◽  
Isaac A. Chaim ◽  
Jorge A. Benitez ◽  
Sebastian Markmiller ◽  
Alison D. Parisian ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Tumor Development ◽  
Genetically Engineered ◽  
Longitudinal Assessment

scholarly journals Longitudinal assessment of tumor development using cancer avatars derived from genetically engineered pluripotent stem cells

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Tomoyuki Koga ◽  
Isaac A. Chaim ◽  
Jorge A. Benitez ◽  
Sebastian Markmiller ◽  
Alison D. Parisian ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Tumor Development ◽  
Genetically Engineered ◽  
Longitudinal Assessment

scholarly journals TMOD-28. AUTHENTIC HUMAN GLIOMA MODELING USING GENETICALLY ENGINEERED INDUCED PLURIPOTENT STEM CELLS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi268-vi269
Author(s):  
Tomoyuki Koga ◽  
Isaac Chaim ◽  
Sebastian Markmiller ◽  
Jorge Benitez ◽  
Alison Parisian ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Tumor Heterogeneity ◽  
Molecular Subtype ◽  
Genetic Alterations ◽  
Genetically Engineered ◽  
Patient Treatment ◽  
Human Glioma ◽  
Induced Pluripotent

Abstract Many mouse and human glioma models have been utilized to study the genetic alterations involved in the genesis of these tumors, but they have not been fully evaluated for how closely they recapitulate pathobiology, including tumor heterogeneity, which is an inherent feature making patient treatment difficult. Here we present new glioma models using genetically engineered human pluripotent stem cells, in which authentic pathobiology is recapitulated through precision gene editing. Specifically, we show that neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs), with different combinations of genetic drivers introduced by CRISPR/Cas9-mediated editing give rise to distinct intracranial tumors recapitulating authentic pathobiology of the disease when engrafted in immunocompromised mice. NPCs deficient in PTEN and NF1, a genotype associated with the mesenchymal molecular subtype, and NPCs deficient in TP53 and expressing a PDGFRA activating mutation (PDGFRAΔ8–9), a genotype associated with the proneural glioblastoma molecular subtype, give rise to distinct tumors resembling glioblastoma. Both models presented inter and intra-tumor heterogeneity based on single-cell RNA sequencing, with the former model showing proneural signature and the latter a mesenchymal signature, and both having different degrees of cycling, and stem cell-enriched populations. The TP53/PDGFRA model had more clonal variability related with striking karyotype abnormalities including extrachromosomal DNA. Additionally, we expanded this approach to pediatric gliomas. Brainstem tumors derived from NPCs introduced with TP53 R248Q and H3F3A K27M mutations presented features of glial tumors with global expression of histone H3 K27M accompanied by suppression of histone H3K27 trimethylation, compatible with H3 K27M-mutant pediatric diffuse midline glioma. Using these isogenic human brain tumor models, we aim to advance our understanding of the pathobiology associated with different driver mutations and further, to provide a platform for development of targeted therapy.

scholarly journals Cardiomyocytes Derived from Induced Pluripotent Stem Cells as a Disease Model for Propionic Acidemia

2021 ◽  
Vol 22 (3) ◽  
pp. 1161
Author(s):  
Esmeralda Alonso-Barroso ◽  
Belén Pérez ◽  
Lourdes Ruiz Desviat ◽  
Eva Richard
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Ex Vivo ◽  
Disease Model ◽  
Propionic Acidemia ◽  
Heart Tissue ◽  
Altered Expression ◽  
Cellular Models ◽  
Induced Pluripotent

Propionic acidemia (PA), one of the most frequent life-threatening organic acidemias, is caused by mutations in either the PCCA or PCCB genes encoding both subunits of the mitochondrial propionyl-CoA carboxylase (PCC) enzyme. Cardiac alterations (hypertrophy, dilated cardiomyopathy, long QT) are one of the major causes of mortality in patients surviving the neonatal period. To overcome limitations of current cellular models of PA, we generated induced pluripotent stem cells (iPSCs) from a PA patient with defects in the PCCA gene, and successfully differentiated them into cardiomyocytes. PCCA iPSC-derived cardiomyocytes exhibited reduced oxygen consumption, an accumulation of residual bodies and lipid droplets, and increased ribosomal biogenesis. Furthermore, we found increased protein levels of HERP, GRP78, GRP75, SIG-1R and MFN2, suggesting endoplasmic reticulum stress and calcium perturbations in these cells. We also analyzed a series of heart-enriched miRNAs previously found deregulated in the heart tissue of a PA murine model and confirmed their altered expression. Our novel results show that PA iPSC-cardiomyocytes represent a promising model for investigating the pathological mechanisms underlying PA cardiomyopathies, also serving as an ex vivo platform for therapeutic evaluation.

scholarly journals Pancreatic Progenitors and Organoids as a Prerequisite to Model Pancreatic Diseases and Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Meike Hohwieler ◽  
Martin Müller ◽  
Pierre-Olivier Frappart ◽  
Sandra Heller
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Disease Modeling ◽  
Embryonic Stem ◽  
Cell Types ◽  
Genetically Engineered ◽  
Hereditary Diseases ◽  
Pancreatic Diseases ◽  
Pancreatic Progenitors

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are characterized by their unique capacity to stepwise differentiate towards any particular cell type in an adult organism. Pluripotent stem cells provide a beneficial platform to model hereditary diseases and even cancer development. While the incidence of pancreatic diseases such as diabetes and pancreatitis is increasing, the understanding of the underlying pathogenesis of particular diseases remains limited. Only a few recent publications have contributed to the characterization of human pancreatic development in the fetal stage. Hence, most knowledge of pancreatic specification is based on murine embryology. Optimizing and understanding current in vitro protocols for pancreatic differentiation of ESCs and iPSCs constitutes a prerequisite to generate functional pancreatic cells for better disease modeling and drug discovery. Moreover, human pancreatic organoids derived from pluripotent stem cells, organ-restricted stem cells, and tumor samples provide a powerful technology to model carcinogenesis and hereditary diseases independent of genetically engineered mouse models. Herein, we summarize recent advances in directed differentiation of pancreatic organoids comprising endocrine cell types. Beyond that, we illustrate up-and-coming applications for organoid-based platforms.

scholarly journals An improved method to produce clinical scale natural killer cells from human pluripotent stem cells

2019 ◽  
Author(s):  
Huang Zhu ◽  
Dan S. Kaufman
Keyword(s):  
Stem Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Pluripotent Stem Cells ◽  
Nk Cell ◽  
Embryonic Stem ◽  
Human Pluripotent Stem Cells ◽  
Genetically Engineered ◽  
Cell Populations ◽  
Clinical Scale

AbstractHuman natural killer (NK) cell-based adoptive anti-cancer immunotherapy has gained intense interest with many clinical trials actively recruiting patients to treat a variety of both hematological malignancies and solid tumors. Most of these trials use primary NK cells isolated either from peripheral blood (PB-NK cells) or umbilical cord blood (UCB-NK cells), though these sources require NK cell collection for each patient leading to donor variability and heterogeneity in the NK cell populations. In contrast, NK cells derived human embryonic stem cells (hESC-NK cells) or induced pluripotent stem cells (hiPSC-NK cells) provide more homogeneous cell populations that can be grown at clinical scale, and genetically engineered if desired. These characteristics make hESC/iPSC-derived NK cells an ideal cell population for developing standardized, “off-the-shelf” immunotherapy products. Additionally, production of NK cells from undifferentiated human pluripotent stem cells enables studies to better define pathways that regulate human NK cell development and function. Our group previously established a stromal-free, two-stage culture system to derive NK cells from hESC/hiPSC in vitro followed by clinical-scale expansion of these cells using interleukin-21 expressing artificial antigen-presenting cells. However, prior to differentiation, this method requires single cell adaption of hESCs/hiPSCs which takes months. Recently we optimized this method by adapting the mouse embryonic fibroblast-dependent hESC/hiPSC to feeder-free culture conditions. These feeder-free hESC/hiPSCs are directly used to generate hemato-endothelial precursor cells. This new method produces mature, functional NK cells with higher efficiency to enable rapid production of an essentially unlimited number of homogenous NK cells that can be used for standardized, targeted immunotherapy for the treatment of refractory cancers and infectious diseases.

scholarly journals Intra-tumor heterogeneity and clonal exclusivity in renal cell carcinoma

2018 ◽  
Author(s):  
Ariane L. Moore ◽  
Jack Kuipers ◽  
Jochen Singer ◽  
Elodie Burcklen ◽  
Peter Schraml ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Tumor Heterogeneity ◽  
Tumor Development ◽  
Treatment Strategies ◽  
Evolutionary Process ◽  
Tumor Evolution ◽  
Cell Renal Cell Carcinoma ◽  
Gene Pairs

AbstractTumorigenesis is an evolutionary process in which different clones evolve over time. Interactions between clones can affect tumor evolution and hence disease progression and treatment outcome. We analyzed 178 tumor samples in 89 clear cell renal cell carcinoma patients and found high intra-tumor heterogeneity with 62% of mutations detected in only one of two biopsies per patient. We developed a novel statistical test to identify gene pairs that are altered in co-occurring clones of the same tumor, including the pairsTP53andMUC16, as well asBAP1andTP53. The mutations in these gene pairs are clonally exclusive meaning that they occurred in different branches of the tumor phylogeny, suggesting a synergistic effect between the two clones carrying these mutations. Our analysis sheds new light on tumor development and implies that clonal interactions are common within tumors, which may eventually open up novel treatment strategies to improve cancer treatment.

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