The liver is unique per its capacity to regenerate, and its highly immune-tolerant functions. Kupffer cells (KCs), the tissue resident macrophages of the liver, are critical to maintain liver homeostasis and to promote hepatocyte proliferation during regeneration. Interestingly, KCs share similarities with microglia as their embryological origin (yolk sac), and their high plasticity following tissue injury.
HCCs typically develop in the context of inflamed, injured livers that share traits with chronic regeneration, suggesting that infiltration of innate immune cells occur, as seen during liver regeneration. However, whether the origin of macrophages and the regulation of their function/polarization are connected to their roles in responding to simultaneous inflammation and cancer initiation remains to be determined. Using mouse models of liver regeneration and transposon-based expression of oncogenes/ tumor suppressors relevant to HCC, we hope to determine the spatiotemporal involvement of tissue resident and infiltrating TAMs in HCC progression and recurrence following therapy. We strongly believe that unraveling liver macrophage dynamic pro-tumorigenic functions will allow us to efficiently target their interactions with cancer cells.