Deterministic Role of FOXF2 in Organ-Specific Macrometastasis Transition

The mechanisms contributing to metastasis tropism in breast cancer are far from being understood. The ability of cancer cells to adapt to new microenvironments plays a crucial role in that process. In this issue of Cancer Research, Jiang and colleagues explored the tumor-intrinsic differences that affect seeding and tissue colonization by focusing on two major sites of breast cancer metastasis: the lung and bone. They used genetic approaches and metastasis modeling to assess the role of forkhead box F2 (FOXF2) in remodeling the tumor microenvironment and promoting metastasis outgrowth. Their findings suggest that FOXF2 promotes a micrometastasis-to-macrometastasis transition in bones through the direct activation of NF-κB and BMP4 signaling pathways, independently of tumor subtype. In contrast, FOXF2 was found to hinder the ability of basal models to colonize the lung microenvironment through inhibition of TGFβ signaling. Collectively, these findings underscore the subtype-specific and tissue-dependent roles of FOXF2 in organotropism. See related article by Jiang et al., p. 644.