MYCN reprograms postnatal cells toward embryonic-like transcriptional states and drives tumorigenesis.

The embryonic-like features of neuroblastoma are commonly explained by a developmental arrest model, in which neural crest-derived progenitors undergo transformation after failing to complete normal sympathoadrenal differentiation. Whether such features can instead be actively imposed on postnatal cells during tumor development remains unclear. Here, we show that Mycn, but not c-Myc, induced adrenal tumors after activation in adult tyrosine hydroxylase-positive cells, accompanied by repression of differentiated programs and acquisition of embryonic cell-like features. Similarly, in adult hepatocytes, Mycn induced embryonic transcriptional programs and generated tumors with both hepatocytic and ductal features, consistent with acquisition of an immature, bipotential state. Time-resolved chromatin profiling revealed that early MYCN binding was relatively enriched at AP-1 motif-containing distal regulatory regions associated with subsequent transcriptional repression, whereas later binding showed greater enrichment at canonical E-box-containing promoters, indicating stepwise rewiring of transcriptional programs. Mycn-induced transcriptional signatures also identified aggressive human neuroblastomas, including a subset without MYCN amplification, and a poor-prognosis subset of hepatocellular carcinomas. These findings demonstrate that MYCN can actively impose embryonic-like transcriptional programs on postnatal cells and thereby promote tumorigenesis.