Role of tumor-derived exosomes on reprogramming myeloid cells

A critical phase of tumor progression is represented by metastases, which are one of the leading causes of cancer-related death. In this process, the intercellular communication plays a fundamental role to promote the formation of a suitable microenvironment for tumor cell implantation and growth in a secondary site, thus leading to the establishment of a pre-metastatic niche (pMN). Interestingly, immune cells, and in particular the myeloid compartment, play a dominant role in the pMN formation. Over the last decades, humanized immune-reconstituted (HIR) mouse models have greatly enhanced the understanding of human cancer biology: the infusion of human hematopoietic stem cells (HSC) in immunodeficient mice allowed to obtain engineered models to study in vivo the interaction between the immune system and human cancer. Exploiting the new technology of single-cell RNA sequencing (sc-RNA seq), we deeply investigated the molecular changes that occur in the immune cells within the lung metastatic site in a pancreatic cancer model. In tumor-bearing mice an enrichment in biological processes of vesicles-mediated transport together with the increased expression of chemotactic factors (S100 proteins) in the monocyte population was unveiled. Indeed, we demonstrated the modulation of human monocytes by soluble factors, i.e. tumor-derived exosomes (TEXs), which resulted in the acquisition of pro-metastatic features, probably induced by molecules transported within TEXs. The inhibition of exosomes secretion with GW4869 administration in tumor-bearing HIR mice did not elicit an impairment in metastases formation. In contrast, by blocking a member of S100 protein family, i.e. S100A9, we were able to dampen the generation of a suitable microenvironment for the pMN formation in tumor-bearing, HIR mice. Finally, we demonstrated the potential role of S100A9 as a cancer biomarker to discriminate the clinical outcome of pancreatic cancer patients, both at molecular and protein level. Collectively, we proved that in the early phases of the pMN formation the immature myeloid compartment exerts a pro-metastatic behaviour in response to TEXs, promoting a more aggressive phenotype with the ability to evade the immunosurveillance and favour the metastatic spread.