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.