Figure 6. Proposed model for site-specific regulation of MAM phenotypes in intracranial metastases.

Metastatic site-specific stroma is likely implicated in the establishment of site-specific molecular profiles in cancer cells, which then co-determine MAM phenotypes. The top 3 up-regulated cytokines/chemokines in cancer cells growing at the dura and within brain parenchyma, as well as differences in macrophage polarization markers between the two sites are indicated. Notably, we demonstrated a functional link between LTβ and MAM polarization within the brain parenchyma, while the functions of other cytokines remain to be determined. Based on our findings and evidence from the literature, we propose that MAM activation state is co-determined by the metastatic site-specific cancer cell characteristics (e.g. cytokines), the organ-specific stroma, and by the origin of macrophages (e.g. Gr1⁺Ly6C^high inflammatory monocytes versus Ly6C^low resident monocytes [20]).