Innervated tumors are frequently more aggressive than less innervated ones. The nervous system is an active participant in carcinogenesis and cancer progression but the mechanistic understanding of how tumors obtain their neural elements remains unclear. Schwann cells, the main population of glial cells of the peripheral nerves, drive and support axonal growth towards the target during development and after injury. These cells are often found disperse in the tumor stroma altering tumor microenvironment and fostering cancer progression. Our previous results demonstrate that the neurotrophic properties of Schwann cells can be modulated by thrombin which acts through its main receptor, the protease activated-receptor-1 (PAR1) (Pompili et al., 2017; Pompili et al., 2020). Aim of the present project is to analyse the contribution of the thrombin/PAR1 axis at the crosstalk between Schwann cells and some neurotropic tumors, such as pancreatic adenocarcinomas. It is imperative to fill knowledge gaps related to comorbidities, mechanisms of pathogenesis, and pathways rendering some tumors, such as pancreatic cancer, refractive to therapy in order to improve the medical management of this deadly disease.
Cancer-nerve crosstalk is an underappreciated area of cancer research, but nerves are now gaining attention for their role in cancer, as researchers discover their connection to cancer metastasis and poor prognosis. Like most cancer studies, these crosstalk interactions have mostly been observed in patient samples and animal models at this point, making it difficult to understand the mechanisms in a controlled manner. As such, in recent years in vitro studies have emerged that have helped identify various microenvironmental factors responsible for cancer-nerve crosstalk, including but not limited to neurotrophic factors, neurotransmitters, chemokines, cancer-derived exosomes, and Schwann cells. In this connection, our project will use an in vitro system in order to clarify the contribution of Schwann cell activation by thrombin in favouring the growth and survival of pancreatic cancer cells. In vitro models can provide highly reproducible outcomes and are ethically
preferred over in vivo models while allowing researchers to control the contribution of specific components of the cellular microenvironment (such as thrombin), which makes them advantageous over in vivo models.
RNA sequencing analysis of thrombin-activated human Schwann cells will allow the identification of novel factors capable of fostering pancreatic cancer cell growth. The aggressive and invasive properties of pancreatic cancer contribute to its high mortality rate. Thus, it is imperative to fill knowledge gaps related to mechanisms of pathogenesis, and pathways rendering pancreatic cancer refractive to therapy in order to improve surgical and medical management of this deadly disease.