In this issue of the JCI, Sansone et al. () show that the tumorigenic conversion of mammary stem cells (CD44^hiCD24^lo) results in an increase in IL-6 expression and secretion. IL-6 secretion results in a positive feedback loop causing further IL-6 upregulation and secretion. Once secreted, IL-6 can bind the IL-6 receptor (IL-6R), causing the upregulation of the Notch-3 ligand Jagged-1, which triggers the upregulation of CA-IX. While not depicted here, it should be noted that Jagged-1 is a transmembrane ligand. The result of these changes is the promotion of malignant features in these mammary stem cells. Also in this issue, Gao et al. () show that EGFR mutations in lung adenocarcinoma cells cause an increase in IL-6 expression and secretion. This, in turn, promotes malignant features in these cells through the IL-6 receptor activation–mediated phosphorylation of STAT3.