Identification of potential myeloid cell-related biomarkers of early stage of metastatic process in pancreatic tumor.

During cancer progression, tumor cells acquire a high number of genetic and epigenetic alterations, which promote a more aggressive phenotype with the ability to escape from immune surveillance. One of the most efficient mechanism of evasion is the capacity of tumor cells to alter the normal hematopoiesis by the continuous release of tumor-derived secreted factors (TDSFs) including cytokines, chemokines and metabolites. Indeed all these metabolites induce an abnormal expansion and accumulation of immature myeloid cells with immunosuppressive features like myeloid-derived suppressor cells (MDSC) and tumor associated macrophages (TAM), which can promote tumor growth and distal dissemination inducing the formation of a suitably conducive microenvironment at secondary sites (pre-metastatic niche). The pre-metastatic niche formation has been well characterized in cancer mouse model but its presence in human patients has to be confirmed yet. Using a humanized immune reconstituted (HIR) mice, engrafted with human hematopoietic stem cells (HSC), we demonstrated that the presence of a human immune system increased the metastatic potential of a human pancreatic tumor cell line compared to tumor-bearing immunodeficient mice. Human leukocytes that infiltrated the lung early-metastatic niche in HIR pancreatic tumor-bearing mice were characterized by a gene signature strongly related to the myeloid cell compartment. Indeed, we detected a myeloid cell population that were exclusively present in bone marrow (BM), lung, blood and spleen of tumor-bearing HIR mice which present a peculiar profile of human cytokines and chemotactic factors involved in the recruitment of tumor cells toward the metastatic niche. This gene signature allowed us to identify potential molecular targets playing a role in the control of tumor cells aggressiveness and metastatic properties which could be exploited for the development of new therapeutic approaches.