Pancreatic Tumor-Derived Extracellular Vesicles Stimulate Schwann Cell Phenotype Indicative of Perineural Invasion via IL-8 Signaling

Abstract

Pancreatic cancer remains a pre-eminent cause of cancer-related deaths with late-stage diagnoses leading to an 11% five-year survival rate. Moreover, perineural invasion (PNI), in which cancer cells migrate into adjacent nerves, occurs in an overwhelming majority of patients, further enhancing tumor metastasis. PNI has only recently been recognized as a key contributor to cancer progression; thus, there are insufficient treatment options for the disease. Attention has been focused on glial Schwann cells (SC) for their mediation of pancreatic PNI. Under stress, SCs dedifferentiate from their mature state to facilitate the repair of peripheral nerves; however, this signaling can also re-direct cancer cells to accelerate PNI. Limited research has explored the mechanism that causes this shift in SC phenotype in cancer. Tumor-derived extracellular vesicles (TEV) have been implicated in other avenues of cancer development, such as pre-metastatic niche formation in secondary locations, yet how TEVs contribute to PNI has not been fully explored. In this study, we highlight TEVs as initiators of SC activation into a PNI-associated phenotype. Proteomic and pathway assessments of TEVs revealed an elevation in interleukin-8 (IL-8) signaling and nuclear factor kappa B (NF{kappa}B) over healthy cell-derived EVs. TEV-treated SCs exhibited higher levels of activation markers, which were successfully neutralized with IL-8 inhibition. Additionally, TEVs increased NF{kappa}B subunit p65 nuclear translocation, which may lead to increased secretion of cytokines and proteases indicative of SC activation and PNI. These findings present a novel mechanism that may be targeted for the treatment of pancreatic cancer PNI. Statement of SignificanceIdentifying pancreatic tumor extracellular vesicles as key players in Schwann cell activation and perineural invasion by way of IL-8 will educate for more specialized and effective targets for an under-valued disease.