Context-Dependent Effects of Midkine on Plexiform Neurofibroma Growth and Drug Response in 3D Coculture Models

Midkine (MDK) is a heparin-binding growth factor that promotes tumor growth in many cancers and may contribute to type I neurofibromatosis (NF1) tumor by stimulating Schwann cell proliferation and supporting neurofibroma growth. Here, we investigated the role of midkine in plexiform neurofibroma with NF1 (pNF1) using both monoculture and neuron-tumor coculture system with biomimetic neuronal axons engineered to release midkine in 3D. In monoculture, midkine enhanced the growth of pNF1 tumor cells, consistent with its tumor-promoting role in several cancers. In contrast, in 3D coculture, midkine did not increase tumor growth and failed to alter response to selumetinib, the FDA-approved treatment for pNF1. These findings suggest that while midkine promotes tumor growth, its effect may be buffered or neutralized in a neuron-associated microenvironment, underscoring the importance of physiologically relevant models for evaluating therapeutic targets in NF1.