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Human stem cell-based model of MYCN-driven neuroblastoma

Huang, Miller and McHenry, Lauren K. and Miller, Matthew L. and Kim, Grace E. and Moriarity, Branden S. and Miyaoka, Yuichiro and Bronner, Marianne E. and Largaespada, David A. and Conklin, Bruce R. and Ji, Hanlee P. and Maris, John M. and Matthay, Katherine K. and Weiss, William A. (2015) Human stem cell-based model of MYCN-driven neuroblastoma. Cancer Research, 75 (S15). Art. No. 3230. ISSN 0008-5472. https://resolver.caltech.edu/CaltechAUTHORS:20160408-110803385

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Abstract

Neuroblastoma (NB), a disease of neural crest (NC) origin, is the most common extracranial solid tumor in childhood. High-risk NB patients represent the subgroup with the worst prognosis and frequently harbor amplification of MYCN. Due to its biochemical structure as a transcription factor, MYCN has been difficult to target directly with small molecules. Alternatively, identification of cooperating partners of MYCN-induced tumorigenesis can reveal a more therapeutically viable target, such as anaplastic lymphoma kinase (ALK). While genetically engineered mouse models (GEMMs) of NB driven by MYCN and ALK exist, recent studies have found significant differences between mouse models of disease and the human tumors they are intended to represent. In support of this, mouse and human NC cells differ in development and marker expression, and the genetic requirement for transformation of human cells has been shown to be more complex than mouse cells, suggesting that a human cell-based NB model would be more relevant. To develop a human cell-based model of NB, we started with a normal human induced pluripotent stem (iPS) cell line derived integration-free from a healthy adult and transduced empty vector, ALK F1174L (active mutant), doxycycline-inducible MYCN (DOX-MYCN), or ALK F1174L/DOX-MYCN. These iPS cells were differentiated towards NC cells and subsequently implanted orthotopically into renal capsules of mice fed on dox chow. Within 3 months, 60% of mice developed tumors with ALK F1174L/DOX-MYCN, 10% with DOX-MYCN, and 0% with both empty vector and ALK F1174L alone. Tumors were transplantable and demonstrated histologic characteristics consistent with NB, including morphology and expression markers. Thus, we are demonstrating the first, to our knowledge, human stem cell-based model of NB. We are using this system to further investigate similarities and differences with GEMMs of NB, test and establish novel candidate drivers of NB, and evaluate potential therapeutic options.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1158/1538-7445.AM2015-3230DOIArticle
http://cancerres.aacrjournals.org/content/75/15_Supplement/3230PublisherArticle
ORCID:
AuthorORCID
Bronner, Marianne E.0000-0003-4274-1862
Additional Information:© 2015 American Association for Cancer Research.
Issue or Number:S15
Record Number:CaltechAUTHORS:20160408-110803385
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20160408-110803385
Official Citation:Miller Huang, Lauren K. McHenry, Matthew L. Miller, Grace E. Kim, Branden S. Moriarity, Yuichiro Miyaoka, Marianne E. Bronner, David A. Largaespada, Bruce R. Conklin, Hanlee P. Ji, John M. Maris, Katherine K. Matthay, William A. Weiss. Human stem cell-based model of MYCN-driven neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3230. doi:10.1158/1538-7445.AM2015-3230
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66022
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:12 Apr 2016 23:40
Last Modified:03 Oct 2019 09:52

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