Human iPSC modeling recapitulates in vivo sympathoadrenal development and reveals an aberrant developmental subpopulation in familial neuroblastoma
Stéphane Van Haver,
Yujie Fan,
Sarah-Lee Bekaert,
Celine Everaert,
Wouter Van Loocke,
Vittorio Zanzani,
Joke Deschildre,
Inés Fernandez Maestre,
Adrianna Amaro,
Vanessa Vermeirssen,
Katleen De Preter,
Ting Zhou,
Alex Kentsis,
Lorenz Studer,
Frank Speleman,
Stephen S. Roberts
Affiliations
Stéphane Van Haver
Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium
Yujie Fan
The Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA; Developmental Biology Program, MSKCC, New York, NY 10065, USA; Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10065, USA
Sarah-Lee Bekaert
Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium
Celine Everaert
Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium
Wouter Van Loocke
Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium
Vittorio Zanzani
Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Lab for Computational Biology, Integromics and Gene Regulation (CBIGR), Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium
Joke Deschildre
Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Lab for Computational Biology, Integromics and Gene Regulation (CBIGR), Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium
Inés Fernandez Maestre
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Louis V. Gerstner Jr Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Adrianna Amaro
Department of Pediatrics, MSKCC, New York, NY 10065, USA
Vanessa Vermeirssen
Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Lab for Computational Biology, Integromics and Gene Regulation (CBIGR), Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium
Katleen De Preter
Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium
Ting Zhou
The SKI Stem Cell Research Facility, The Center for Stem Cell Biology and Developmental Biology Program, Sloan Kettering Institute, 1275 York Avenue, New York, NY 10065, USA
Alex Kentsis
Department of Pediatrics, MSKCC, New York, NY 10065, USA; Molecular Pharmacology Program, MSKCC, New York, NY, USA; Tow Center for Developmental Oncology, MSKCC, New York, NY 10065, USA; Departments of Pediatrics, Pharmacology and Physiology & Biophysics, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA
Lorenz Studer
The Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA; Developmental Biology Program, MSKCC, New York, NY 10065, USA
Frank Speleman
Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium
Stephen S. Roberts
Department of Pediatrics, MSKCC, New York, NY 10065, USA; Corresponding author
Summary: Studies defining normal and disrupted human neural crest cell development have been challenging given its early timing and intricacy of development. Consequently, insight into the early disruptive events causing a neural crest related disease such as pediatric cancer neuroblastoma is limited. To overcome this problem, we developed an in vitro differentiation model to recapitulate the normal in vivo developmental process of the sympathoadrenal lineage which gives rise to neuroblastoma. We used human in vitro pluripotent stem cells and single-cell RNA sequencing to recapitulate the molecular events during sympathoadrenal development. We provide a detailed map of dynamically regulated transcriptomes during sympathoblast formation and illustrate the power of this model to study early events of the development of human neuroblastoma, identifying a distinct subpopulation of cell marked by SOX2 expression in developing sympathoblast obtained from patient derived iPSC cells harboring a germline activating mutation in the anaplastic lymphoma kinase (ALK) gene.
