Abstract B48: A LIN28B-PDZ kinase axis promotes neuroblastoma metastasis

Background: Neuroblastoma, an aggressive cancer of the developing sympathetic nervous system, continues to cause significant morbidity and mortality, highlighting the need to identify novel therapeutic vulnerabilities. We previously demonstrated that the RNA binding protein (RBP) LIN28B is an oncogenic driver and induces neuroblastoma proliferation, in part by regulating a RAN GTPase-Aurora kinase A axis. LIN28B blocks the processing of the let-7 family of tumor suppressors and binds mRNAs directly. In addition to alterations in cell cycle/apoptosis, metastatic dissemination is a hallmark of cancer that is incompletely understood, and neuroblastoma exhibits a striking proclivity for widespread metastases. In these studies, we investigated how LIN28B shapes neuroblastoma metastasis. Methods: We generated GFP-luciferase expressing neuroblastoma cell line models in which LIN28B levels were manipulated, injected these models into the tail veins of NSG mice, and tracked dissemination using an IVIS Spectrum system. We used gain- and loss-of-function approaches (siRNAs, shRNAs, microRNA mimetics) to manipulate transcripts of interest in neuroblastoma cells and measured effects on self-renewal, invasion, and downstream signaling. To discover LIN28B-associated pathways, we assessed clinically annotated mRNA expression datasets. Results: Mice injected with LIN28B-depleted neuroblastoma cells exhibit a delayed onset of tumor metastasis, reduced tumor burden, and extended survival (103 days vs. 50 days, p