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

doi:10.1016/j.isci.2023.108096

Human iPSC modeling recapitulates in vivo sympathoadrenal development and reveals an aberrant developmental subpopulation in familial neuroblastoma

iScience. 2023 Sep 30;27(1):108096. doi: 10.1016/j.isci.2023.108096. eCollection 2024 Jan 19.

Authors

Stéphane Van Haver^{1

2}, Yujie Fan^{3

4

5}, Sarah-Lee Bekaert^{1

2}, Celine Everaert^{1

2}, Wouter Van Loocke^{1

2}, Vittorio Zanzani^{1

6

7}, Joke Deschildre^{1

6

7}, Inés Fernandez Maestre^{8

9}, Adrianna Amaro¹⁰, Vanessa Vermeirssen^{1

6

7}, Katleen De Preter^{1

2}, Ting Zhou¹¹, Alex Kentsis^{10

12

13

14}, Lorenz Studer^{3

4}, Frank Speleman^{1

2}, Stephen S Roberts¹⁰

Affiliations

¹ Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium.
² Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium.
³ The Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.
⁴ Developmental Biology Program, MSKCC, New York, NY 10065, USA.
⁵ Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10065, USA.
⁶ Lab for Computational Biology, Integromics and Gene Regulation (CBIGR), Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
⁷ Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium.
⁸ Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁹ Louis V. Gerstner Jr Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁰ Department of Pediatrics, MSKCC, New York, NY 10065, USA.
¹¹ 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.
¹² Molecular Pharmacology Program, MSKCC, New York, NY, USA.
¹³ Tow Center for Developmental Oncology, MSKCC, New York, NY 10065, USA.
¹⁴ Departments of Pediatrics, Pharmacology and Physiology & Biophysics, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA.

Abstract

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.

Keywords: Cancer; Stem cells research.

Abstract

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