The role of exosome-mediated crosstalk between cancer cells and nerves in pancreatic cancer

• Applicants: Professor Dr. Ihsan Ekin Demir; Professor Dr. Christoph Kahlert
• Subject Area: General and Visceral Surgery
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 463450523

Pancreatic cancer (PDAC) is widely recognized as one of the most deadly cancer. While metastasis to secondary organs is common in PDAC, it also exhibits a high frequency of cancer cell penetration into nerves, employing another mode of metastasis. This special route of metastasis has been known as neural invasion (NI). It has become one of the hallmarks of PDAC because it is frequently associated with a dismal prognosis. In the current proposal, we aim to investigate if the exosome-mediated crosstalk between pancreatic cancer cells and the perineural microenvironment have an effect on tumor progression. By the release of exosomes, cancer cells can shuttle oncogenic molecules to recipient cells and the extracellular matrix, altering the local and systemic tumor microenvironment in support of cancer. However, the exosome-mediated crosstalk between cancer cells and nerves and the impact on the NI in pancreatic cancer remains elusive. Thus, the principle of this proposal will be to investigate how tumor-derived exosomes reprogram the nerve microenvironment to induce NI. In Aim1.1, we will test the hypothesis that pre-conditioning of Schwann cells and neurons with exosomes from neural invasive pancreatic cells and/or activated fibroblasts (pancreatic stellate cells) will increase the neuro-invasiveness of pancreatic cancer cells in vitro and in vivo. To further understand how PDAC-derived exosomes support the neural invasion, we will disrupt the exosomal crosstalk by targeting different pathways in vivo. This will help also to elucidate if the impairment of the exosome function might be a potential target in cancer therapy. In Aim1.2, we want to evaluate if exosomes from PDAC cells with high and low NI-potential can determine neurotropism. We aim to identify exosome-associated molecules that can increase NI. Subsequently, we will investigate if targeting those specific exosomal markers can reduce neural invasion. In Aim 2, we will investigate the reciprocal impact of Schwann cell-derived exosomes on neuro-invasiveness of cancer cells. This is a novel concept since up-to-date, the majority of the studies has focused only on the role of the unidirectional exosomal transfer from tumor cells on the (neural) microenvironment. These data can provide a new perspective of the exosome-mediated invasive behaviour and will further assess the role of the tumor microenvironment on tumor progression in pancreatic cancer. Moreover, we plan to identify NI-promoting targets in Schwann cell-derived exosomes that can be targeted to inhibit the activation and tumor-promoting effect in recipient PDAC cells. The results of Aim 1 and Aim 2 will help to identify potential diagnostic and predictive markers, which we plan to validate in a large cohort of patients with pancreatic cancer in Aim 3. These data would provide a novel approach to stratify patients into different risk categories and to improve the diagnosis for the early detection of recurrent PDAC.

• DFG Programme: Research Grants