GRPR-induced FAM135A expression promote perineural invasion in prostate cancer

Perineural invasion (PNI) is an independent adverse prognostic marker for prostate cancer (PCa) metastasis. Gastrin releasing peptide receptor (GRPR) targeted imaging and therapeutics have entered clinical trials, while its role in PCa perineural invasion remains unclear. Here, we uncovered Family With Sequence Similarity 135 Member A ༈FAM135A༉a dominant PNI driver activated by GRPR in PCa. First, PNI-PCa tissue showed higher neuroactive ligand-receptor interaction activity, and with FAM135A being the most notable marker in PNI group. Then in-vitro experiments using a co-culture system of PCa cells (including AR-positive LNCaP and AR-negative DU145/PC3) showed that FAM135A silencing abrogated tumor malignancy and neural invasion. Moreover, in vivo PCa-Sciatic nerve invasion mouse model demonstrated FAM135A inhibition controls tumor growth and improves motor function. Interestingly, FAM135A is nucleus enriched and its nuclear translocation is mediated by protein cytoplasmic-nuclear transporter RAN. Mechanistically, RNA-Seq and ChIP-Seq analyses identified Teneurin Transmembrane Protein 3 (TENM3) as a transcriptional target of nFAM135A, and TENM3 plays an essential role in nFAM135A-induced cancer-nerve invasion. Notably, FAM135A is ultimately activated by Gastrin Releasing Peptide GRP and its receptor GRPR. Moreover, pharmacological GRPR inhibitor represses FAM135A expression via MED15 activation. Together, we unveil FAM135A as an oncodriver and biomarker of PCa perineural invasion, and provide a novel strategy for PCa innervation therapeutics.