Oncotarget

Research Papers:

Down syndrome iPSC model: endothelial perspective on tumor development

Mariana Perepitchka _, Yekaterina Galat _, Igor P. Beletsky, Philip M. Iannaccone and Vasiliy Galat _

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Abstract

Mariana Perepitchka1,2, Yekaterina Galat1,2,3,*, Igor P. Beletsky3, Philip M. Iannaccone1,2,4,5 and Vasiliy Galat2,3,4,5,6

1 Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

2 Developmental Biology Program, Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital, Chicago, IL, USA

3 Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia

4 Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

5 Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

6 ARTEC Biotech Inc, Chicago, IL, USA

* Co-first author

Correspondence to:

Mariana Perepitchka,email: mperepitchka@u.northwestern.edu
Yekaterina Galat,email: ygalat@luriechildrens.org
Vasiliy Galat,email: v-galat@northwestern.edu

Keywords: Down syndrome; iPSC-derived endothelial model; T21 genome-wide Implications; meta-analysis; tumor microenvironment

Received: July 10, 2019     Accepted: August 01, 2020     Published: September 08, 2020

ABSTRACT

Trisomy 21 (T21), known as Down syndrome (DS), is a widely studied chromosomal abnormality. Previous studies have shown that DS individuals have a unique cancer profile. While exhibiting low solid tumor prevalence, DS patients are at risk for hematologic cancers, such as acute megakaryocytic leukemia and acute lymphoblastic leukemia. We speculated that endothelial cells are active players in this clinical background. To this end, we hypothesized that impaired DS endothelial development and functionality, impacted by genome-wide T21 alterations, potentially results in a suboptimal endothelial microenvironment with the capability to prevent solid tumor growth.

To test this hypothesis, we assessed molecular and phenotypic differences of endothelial cells differentiated from Down syndrome and euploid iPS cells. Microarray, RNA-Seq, and bioinformatic analyses revealed that most significantly expressed genes belong to angiogenic, cytoskeletal rearrangement, extracellular matrix remodeling, and inflammatory pathways. Interestingly, the majority of these genes are not located on Chromosome 21. To substantiate these findings, we carried out functional assays. The obtained phenotypic results correlated with the molecular data and showed that Down syndrome endothelial cells exhibit decreased proliferation, reduced migration, and a weak TNF-α inflammatory response. Based on this data, we provide a set of genes potentially associated with Down syndrome’s elevated leukemic incidence and its unfavorable solid tumor microenvironment—highlighting the potential use of these genes as therapeutic targets in translational cancer research.


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