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Cell Signaling Pathway Identified as Metastasis Suppressor

The discovery of a cell signaling pathway's role in stopping the reactivation of dormant cancer cells that have escaped from a primary tumor is reported in Nature this week and may represent a new therapeutic target for combating metastasis. Metastasis, the primary cause of death from cancer, frequently develops from disseminated cancer cells that persist in an immune-evasive quiescent state months to years after a primary tumor is successfully treated, only to reawaken. To investigate this process further, scientists from Memorial Sloan Kettering Cancer Center performed CRISPR screens in mouse models of early lung cancer metastasis to identify genes that affect how tumor cells interact with the host immune system. They discover that the stimulator of interferon genes, or STING, pathway suppresses metastatic outbreaks. Notably, STING activity changes at different stages of metastasis, remaining low when cancer cells are dormant and ramping up when they proliferate. Further experimentation showed how STING recruits key immune cells to attack cancer and how the signaling molecule TGF-beta acts to suppress STING in quiescent disseminated cancer cells. The study's authors note that a number of STING agonists are currently under clinical investigation, but in patients with advanced tumors. "The dormant metastasis microenvironment is very different from that of the advanced metastases," they write. "Targeting specific vulnerabilities of dormant metastasis in the adjuvant setting may provide unique opportunities to prevent metastasis."