The researchers designed an in vitro co-culture system and an in vivo co-culture system. Based on these systems, they discovered that breast cancer stem cells (BCSCs) inhibit their own capacity through a BSCS-derived secretory system. Using screening, bioluminescence imaging and other methods, they also discovered that DKK1 plays an important role in the cryptosystem. DKK1 was identified as an important molecule that can dynamically reduce the CSC population and subsequently promote breast cancer metastasis.
Further experiments showed that this autorepression of BCSCs can promote disseminated tumor cells (DTCs), which are mostly inactive after reaching distant sites, out of the state. hibernation and then achieve metastasis. However, a small molecule inhibitor of DKK1 was able to almost completely suppress lung metastasis in multiple BCSC metastasis models.
Ferroptosis, an aberrant cell death, is caused by abnormal metabolism and lipid peroxidation. Compared with primary breast cancer cells, lung metastatic cancer cells are subject to higher oxidative and ferroptotic stress. The researchers revealed that highly invasive CSCs were present in relatively high concentrations in lung metastases, where CSCs were able to secrete DKK1 to repress CSCs. As CSCs are highly susceptible to ferroptosis, CSC-secreted DKK1 protects cells in lung metastases from ferroptosis and thus contributes to increased metastasis.
The findings of this study suggest a role for CSC-regulated phenotypic plasticity in metastatic metastasis, and provide novel therapeutic approaches to effectively inhibit metastasis.