Fig. 1

Metastatic cascade during PDAC progression. A Cells disseminating from primary tumors preferentially metastasize to different organs such as the liver (A) and lung (B). C Several TME factors such as hypoxia, autophagy, and suppressive cytokines and chemokines influence tumor cells to undergo EMT and gain immunosuppressive phenotype with reduced expression of MHCI and epithelial markers and increased PD-L1 expression. D, E Immunological dormancy, metabolic switch, and activation of metastasis-associated kinases promote disseminating cells to metastasize to different organs having a pre-metastatic niche for the initiation of metastasis (PMN in the liver is illustrated in the figure). F Several factors, including exosomes, miRs, and immune cell secreted factors, such as MIF, cytokines, and various chemokines, guide the development of PMN. G, H Hepatic stellate cells and Kupffer cells initiate fibrosis at the early stages of PMN development, and different chemokines, MMPs, and cytokines facilitate adaptation of tumor cells to the PMN. I Liver metastasis with different immune cells and metastasis-associated fibroblasts and resident hepatic cells. Abbreviations: PMN- pre-metastatic niche; MHC- major histocompatibility complex; EMT- epithelial to mesenchymal transition; PD-L1- programmed death receptor ligand-1; MIF- macrophage migration inhibitory factor; miR- micro-RNA; ncRNA- non-coding RNA; TGFβ- tumor growth factor- β; IL- interleukin; MMP- matrix metalloprotease