Functional ANXA2 regulates SEMA3D secretion, binding and activating the receptor PLXND1 on DRG to increase TC migration and invasion activity.128 Similarly, in cancers of unknown primary (CUP), a novel activating mutation in the axon guidance gene PLXNB2 can maintain proliferative autonomy in an EGFR-dependent manner and confer invasive properties to CSCs isolated from CUP, promoting tumor progression.129 Thus, the identification of axon guidance molecules and axon guidance genes may provide guidance for the development of novel genetic biomarkers for tumor management. The gene discussed is PLXNB2; the disease is neoplasm.