Perineural invasion (PNI) represents a clinically significant and independent indicator of metastatic risk in prostate cancer (PCa). Although gastrin-releasing peptide receptor (GRPR)–directed imaging and therapeutic approaches are currently under clinical evaluation, the contribution of GRPR signaling to PNI in PCa has not been fully elucidated. In this study, we identify Family With Sequence Similarity 135 Member A (FAM135A) as a key GRPR-activated regulator driving PNI in PCa. Transcriptomic analyses revealed enhanced neuroactive ligand–receptor interaction signaling in PNI-positive PCa tissues, with FAM135A emerging as the most prominent marker associated with this phenotype. Functional investigations using an in vitro co-culture system incorporating AR-positive (LNCaP) and AR-negative (DU145 and PC3) PCa cell lines demonstrated that suppression of FAM135A markedly reduced malignant behavior and nerve-directed invasion. Consistently, in a PCa sciatic nerve invasion mouse model, inhibition of FAM135A restrained tumor progression and significantly improved motor performance. At the subcellular level, FAM135A was predominantly localized within the nucleus, with its nuclear import dependent on the cytoplasmic–nuclear transport protein RAN. Integrated RNA-Seq and ChIP-Seq analyses further identified Teneurin Transmembrane Protein 3 (TENM3) as a direct transcriptional target of nuclear FAM135A, and TENM3 proved to be essential for FAM135A-mediated cancer–nerve interactions. Importantly, FAM135A expression was shown to be induced by gastrin-releasing peptide (GRP) through GRPR activation, while pharmacological inhibition of GRPR suppressed FAM135A expression via MED15-dependent mechanisms. Collectively, these findings establish FAM135A as a central oncodriver and potential biomarker of PNI in PCa and suggest a novel therapeutic avenue targeting tumor innervation in prostate cancer.
