LMO1 expression in neuroblastoma cells reprograms tumor-associated macrophages to promote metastasis.

Neuroblastoma (NB) accounts for 10% of pediatric cancer-related deaths, is often highly metastatic at diagnosis, and has a 5-year-survival rate of <50% for patients with high-risk disease. We previously showed that the transcriptional coactivator LMO1 cooperates with the MYCN oncogene to enhance NB tumorigenesis and metastasis. To better understand this synergy, we performed single-cell RNA sequencing analysis on primary tumors from transgenic zebrafish overexpressing MYCN alone or with LMO1. Interestingly, we found that the macrophage populations from the two tumor types were transcriptionally distinct, and LMO1 increased cancer-cell secretion of cytokines associated with metastasis and angiogenesis. Conditioned media from LMO1-expressing NB cells activated PI3K-Akt signaling and MMP expression in human macrophages, enhancing matrix degradation and promoting NB cell migration in vivo. Our data suggest that LMO1 overexpression in MYCN-amplified NB cells increases the pro-metastatic properties of macrophages in the tumor-cell microenvironment, which is important for driving NB metastasis.