The 3D cellular organization of Schwann cells during cancer invasion

• Applicant: Dr. Pavel Stupakov
• Subject Area: General and Visceral Surgery
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 491318253

Building on research of the past 10 years, nerves in the cancer microenvironment have emerged as key players for tumor progression. It is known, that nerves enable cancer progression, and the innervation of some cancers promotes growth and metastases. In many solid cancers of the gastrointestinal tract (pancreatic, gastric, esophageal, colorectal cancer), cancer cells are frequently encountered in the perineural sheats (epineurium, perineurium, endoneurium), termed perineural invasion. Cancer cells can also progress and penetrate between the axons and Schwann cells and destroy neural integrity. The severity of neural invasion, i.e. the penetration depth and frequency of cancer cells into the interior of nerves, was shown to be an independent prognostic factor for overall survival in several cancers like pancreatic carcinoma or colorectal cancer. Schwann cells are the main glial cells of the peripheral nervous system that keep peripheral nerve fibres alive. The variety of functions performed by Schwann cells is provided by their ability to reversibly dedifferentiate and re-differentiate into subtypes with different phenotypes. In case of nerve damage, Schwann cells dedifferentiate, lose their ability to myelinate and promote nerve regeneration. It is known that Schwann cells support cancer cells during neural invasion similar to nerve regeneration.Pancreatic ductal adenocarcinoma is one of the most aggressive malignancies with worst prognosis and treatment-resistant, high recurrence rate and a 5-year survival rate of 9%. An important characteristic of pancreatic ductal adenocarcinoma is its high affinity to neurons. Up to 100% of all patients with pancreatic ductal adenocarcinoma have perineural invasion, which is one of the most important factors causing local recurrence, chronic pain and poor survival rate.In this project we will identify the molecular factors that induce Schwann cell reprogramming in cancer, direct their organization and stimulate neural invasion. We will investigate the functional relevance of the transcription factor c-Jun in Schwann cell reprogramming and activation for supporting cancer progression towards nerves. We hypothesize that the activation of the transcription factor AP-1 and one of its components, i.e. c-Jun, in Schwann cells in the presence of a tumor stimulates them to support tumor cells, similar to the process of nerve regeneration. We also hypothesize that targeting the transcription factor c-Jun is a possible way to reduce tumor progression towards nerves and to limit neural invasion.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Richard J. Wong