| First Author | Zhu L | Year | 2024 |
| Journal | Biochim Biophys Acta Mol Basis Dis | Volume | 1870 |
| Issue | 7 | Pages | 167314 |
| PubMed ID | 38936516 | Mgi Jnum | J:351061 |
| Mgi Id | MGI:7665072 | Doi | 10.1016/j.bbadis.2024.167314 |
| Citation | Zhu L, et al. (2024) IFN-gamma-responsiveness of lymphatic endothelial cells inhibits melanoma lymphatic dissemination via AMPK-mediated metabolic control. Biochim Biophys Acta Mol Basis Dis 1870(7):167314 |
| abstractText | The integrity of the lymphatic system is critical for preventing the dissemination of tumor cells, such as melanoma, to distant parts of the body. IFN-gamma is well studied as a negative regulator for lymphangiogenesis, which is strongly associated with cancer metastasis. However, the exact mechanisms underlying this process remain unclear. In the present study, we investigated whether IFN-gamma signaling in lymphatic endothelial cells (LECs) affects tumor cell dissemination by regulating the barrier function of tumor-associated lymphatic vessels. Using LEC-specific IFN-gamma receptor (IFN-gammaR) knockout mice, we found that the loss of IFN-gammaR in LECs increased the dissemination of melanoma cells into the draining lymph nodes. Notably, IFN-gamma signaling in LECs inhibited trans-lymphatic endothelial cell migration of melanoma cells, indicating its regulation of lymphatic barrier function. Further investigations revealed that IFN-gamma upregulated the expression of the tight junction protein Claudin-3 in LECs, while knockdown of Claudin-3 in LECs abolished IFN-gamma-induced inhibition of trans-lymphatic endothelial migration activity. Mechanistically, IFN-gamma inhibits AMPK signaling activation, which is involved in the regulation of fatty acid metabolism. Modulating fatty acid metabolism and AMPK activation in LECs also affected the lymphatic dissemination of melanoma cells, further confirming that this process is involved in IFN-gamma-induced regulation of lymphatic barrier function. These results provide novel insights into how IFN-gamma modulates tight junctions in LECs, inhibiting the dissemination of melanoma cells via the lymphatic vessels. |
