Neuroblastoma (NB) is the most common solid extracranial cancer of childhood and accounts 15% of all pediatric cancer deaths. Little is known about NB cancerogenesis, whereas the pathogenesis has been enigmatic for a long time. Nowadays only few gene defects were identified and associated with this lethal tumor, such as MYCN amplification, ALK activation, ATRX and PHOX2b downregulation. It is widely assumed that primary tumors originate from sympatho-adrenal (SA) lineage development, indeed the majority of cancers arise in the adrenal medulla and in the sympathetic trunk.
The availability of valid preclinical in vivo models is a prerequisite to develop and study novel targeted therapies. Unfortunately the existing murine models, expressing MYCN or ALK oncogenes, resemble only to the MYCN-amplified group of human NB.
Our project aims to shed light on the impact of genetic modifications recurrent in NB along embryonic development of SA lineage. Thus, we want to express oncogenes and to silence tumor suppressors in neural crest stem cells (NCSCs) of murine models. To address our questions we are using Sox10-Cre mouse line, where Cre expression is leaded by Sox10 promoter, marker of NCSCs. Through recombination it is allowed population-specific transcription of proto-oncogenes or knocks out of tumor suppressors.
In our work, we are showing that independent expression of MYCN or ALK in Sox10 expressing cells gives embryo lethality in vivo (P<0.001; P<0.001) blocking neural crest differentiation and tissue maturation. Moreover, in order to explore the oncogenic mechanisms driven by others genetic mutations we are now assessing the impact of ATRX and PHOX2b depletion on NCSCs.