Quantitative imaging of schwannoma captures heterogeneity and accelerates preclinical testing, exposing distinct therapeutic signatures

Schwannomas are debilitating hallmarks of familial schwannomatoses and common sporadic tumors that form on spinal and cranial nerves. Drug-based therapies for schwannoma are desperately needed but their development has been extremely slow and disappointing, impeded particularly by the poorly understood and surprisingly complex and heterogeneous biology of schwannomas, and by the inefficient use of physiologically relevant in vivo preclinical models. We have addressed these gaps by developing a quantitative imaging-centered workflow that allows both a deep analysis of schwannoma development and accelerated preclinical testing in a widely used genetically engineered mouse model of neurofibromatosis type 2-related schwannomatosis (NF2-SWN). We deployed our workflow to study schwannoma development and to test three clinically relevant drugs head-to-head. Our results uncovered the very early onset of heterogeneity and macrophage recruitment to initiating schwannomas and unexpectedly revealed that although all three drugs inhibited proliferation within the developing schwannomas, they did so while triggering one of two distinct response signatures, highlighting the value of our pipeline for both rapid drug-testing and translational discovery.