Talin1 Mediates Tumor-Nerve Interactions in Prostate and Breast Cancer Cells.

Prostate cancer (PCa) and breast cancer (BCa) are the leading causes of death in men and women in the US. Neurite outgrowth is a fundamental process in differentiating neurons and contributes to cancer progression. Snail transcription factor promotes cancer progression and regulates neurite outgrowth in PCa cells, but their molecular mechanisms are not fully understood. We hypothesize that Snail can stimulate neurite outgrowth through the secretion of extracellular vesicles. To test this hypothesis, we isolated exosomes from PCa (C4-2 non-silencing (NS) control and C4-2 Snail knockdown) and BCa (MCF7 Neo control and MCF7 Snail overexpressing) cells, which were confirmed by western blot analysis and Transmission Electron Microscopy. Proteomics of isolated exosomes from Snail-expressing C4-2 cancer cells shows predominantly Talin1 proteolyzed C-terminal rod domain and N-terminal head domain within exosomes, while full-length Talin1 is found in whole cell lysates. A significantly higher percentage of NPC (Neural Progenitor Cells) with neurite outgrowth is observed when cultured with conditioned medium or exosomes collected from C4-2 NS PCa or MCF7 Snail BCa cells expressing high levels of Snail compared to C4-2 Snail knockdown or MCF7 Neo, respectively. A similar trend is observed for increased average neurite length due to Snail expression. Furthermore, we find that mH4, a specific inhibitor of proteolyzed Talin1, reduces Snail-induced neurite outgrowth and AKT activation within neurons. Overall, Snail may promote cancer-nerve interactions via Talin1, indicating that Talin1 inhibitors can be a potent targeted therapy in malignant tumors with neurite outgrowth.