The 3D cellular organization of Schwann cells during cancer invasion
Final Report Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal disease with bad prognosis, treatment resistance and high recurrence rate. PDAC is characterized by a multi-faceted fibrotic tumor microenvironment and an explicit involvement of nerves in tumor progression. While pancreas is a poorly innervated organ, PDAC is associated with axonogenesis, innervation and perineural invasion (PNI), i.e. the penetration of cancer cells into the interior of nerves. Schwann cells (SCs) are the major population of cells in peripheral nerves and an important component of the tumor microenvironment. SCs become activated in PDAC through the activation of the transcription factor c-Jun after its phosphorylation. Activated SCs promote PNI. In this project, we characterized the activation of SCs in PDAC, showed stromal impact on their activation and proposed two pathways of activation. We used a Jun kinase reporter to assess c-Jun activation in live SCs in vivo in fibrotic and normal pancreas, as well as in vitro using models mimicking cell confinement in the fibrotic environment. Atomic force microscopy (AFM) was used to assess stiffness of different components of PDAC. Experiments with AFM demonstrated a positive correlation between stroma stiffness and P-c-Jun expression in nerve fibres. We proposed that SCs can be activated in PDAC through two pathways: an activation of SCs induced by cancer cells, that uses a canonical JNK/MAPK pathway through integrins, TNF-α, TGF-β receptors, and another pathway initiated through mechanical forces. The PDAC stroma provides a stiff environment which activates c-Jun via mechanical forces. The mechanosensing machinery is located at the nuclear envelope. It involves phospholipase A2 (Pla2), a player in the eicosanod signaling causing release of arachidonic acid (AA). AA activates kinase SGK1 that phosphorylates c-Jun. Targeting of SC activation can be potentially used for drug development and PNI reduction.
