A MYCN-independent mechanism mediating secretome reprogramming and metastasis in <i>MYCN</i>-amplified neuroblastoma.

Abstract

<i>MYCN</i> amplification (<i>MNA</i>) is a defining feature of high-risk neuroblastoma (NB) and predicts poor prognosis. However, whether genes within or in close proximity to the <i>MYCN</i> amplicon also contribute to <i>MNA⁺</i> NB remains poorly understood. Here, we identify that <i>GREB1</i>, a transcription factor encoding gene neighboring the <i>MYCN</i> locus, is frequently coexpressed with <i>MYCN</i> and promotes cell survival in <i>MNA⁺</i> NB. GREB1 controls gene expression independently of MYCN, among which we uncover myosin 1B (<i>MYO1B</i>) as being highly expressed in <i>MNA⁺</i> NB and, using a chick chorioallantoic membrane (CAM) model, as a crucial regulator of invasion and metastasis. Global secretome and proteome profiling further delineates MYO1B in regulating secretome reprogramming in <i>MNA⁺</i> NB cells, and the cytokine MIF as an important pro-invasive and pro-metastatic mediator of MYO1B activity. Together, we have identified a putative GREB1-MYO1B-MIF axis as an unconventional mechanism promoting aggressive behavior in <i>MNA⁺</i> NB and independently of MYCN.