MOXD1 is a gate-keeper of organ homeostasis and functions as a tumor-suppressor in neuroblastoma

Neuroblastoma is a childhood cancer believed to result from dysfunctional development. Its origin during embryogenesis remains poorly understood. The lack of appropriate models has hindered in-depth mapping of early tumor-driving events. Here, we identify a novel tumor suppressor gene associating with worse outcome in MOXD1-deprived high-risk patients, by applying bulk and single cell RNA sequencing data of neuroblastoma and human fetal adrenal glands. Trunk neural crest-specific MOXD1 discriminates cell populations during normal and tumor development, with implications for deciphering neuroblastoma cell origin. We created an embryonic conditional knockout model and show that cell type-specific loss of MOXD1 leads to disrupted organ homeostasis and failed adrenal gland formation, home for neuroblastoma. We show that MOXD1 is a tumor suppressor gene in zebrafish, chick, and mice in vivo models. To elucidate the transcriptional changes associated with MOXD1 overexpression, we overexpressed MOXD1 in SK-N-BE(2)c cells and performed RNAseq of in vitro grown cells (SK-N-BE(2)cCTRL (n=3) and SK-N-BE(2)cMOXD1-OE (n=3)). We then implanted SK-N-BE(2)cCTRL cells to five mice and SK-N-BE(2)cMOXD1-OE cells to five mice. At experimental endpoint (volume >1800mm3), tumors were dissected and subjected to RNAseq.