Research Papers:

Lineage-restricted sympathoadrenal progenitors confer neuroblastoma origin and its tumorigenicity

Chia-Lung Yang, André Serra-Roma, Marco Gualandi, Nicole Bodmer, Felix Niggli, Johannes Hubertus Schulte, Peter Karl Bode and Olga Shakhova _

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Oncotarget. 2020; 11:2357-2371. https://doi.org/10.18632/oncotarget.27636

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Chia-Lung Yang1, André Serra-Roma1, Marco Gualandi1, Nicole Bodmer2, Felix Niggli2, Johannes Hubertus Schulte3, Peter Karl Bode4 and Olga Shakhova1

1 Department of Medical Oncology and Hematology, University Hospital Zürich, Zürich, Switzerland

2 Department of Oncology, Children Hospital of Zürich, Zürich, Switzerland

3 Department of Pediatric Hematology, Oncology and SCT, Charité University Hospital, Berlin, Germany

4 Department of Surgical Pathology, University Hospital Zürich, Zürich, Switzerland

Correspondence to:

Olga Shakhova,email: [email protected]

Keywords: neuroblastoma; neural crest stem cells; sox geness

Received: March 25, 2020     Accepted: May 20, 2020     Published: June 16, 2020


Neuroblastoma (NB) is the most common cancer in infants and it accounts for six percent of all pediatric malignancies. There are several hypotheses proposed on the origins of NB. While there is little genetic evidence to support this, the prevailing model is that NB originates from neural crest stem cells (NCSCs). Utilizing in vivo mouse models, we demonstrate that targeting MYCN oncogene to NCSCs causes perinatal lethality. During sympathoadrenal (SA) lineage development, SOX transcriptional factors drive the transition from NCSCs to lineage-specific progenitors, characterized by the sequential activation of Sox9/Sox10/Sox4/Sox11 genes. We find the NCSCs factor SOX10 is not expressed in neuroblasts, but rather restricted to the Schwannian stroma and is associated with a good prognosis. On the other hand, SOX9 expression in NB cells was associated with several key biological processes including migration, invasion and differentiation. Moreover, manipulating SOX9 gene predominantly affects lineage-restricted SA progenitors. Our findings highlight a unique molecular SOX signature associated with NB that is highly reminiscent of SA progenitor transcriptional program during embryonic development, providing novel insights into NB pathobiology. In summary, we provide multiple lines of evidence suggesting that multipotent NCSCs do not contribute to NB initiation and maintenance.

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