Supplemental Information to: Aberrant induction of a mesenchymal/stem-cell program engages senescence in normal mammary epithelial cells S1. Cytokine-induced senescence induces EMT and SC-associated gene expression changes. S2. OSM-mediated Snail induction drives an aberrant EMT that induces senescence. S3. OSM-induced EMT requires STAT3- and TGF-β/SMAD3-mediated signaling. S4. Senescence-escape generates transformed CSC which are highly sensitive to palbociclib. S5. Proposed mechanisms of OSM induced senescence, EMT, and stemness in normal human epithelial cells versus transformed cells. S6. Uncropped images of all western blots presented in the current study (continued). Supplementary Table 1. List of primary antibodies used in this study Supplementary Table 2. qRT-PCR primer sequences (listed 5'-to-3') used in this study.
ARTICLE ABSTRACTAlthough frequently associated with tumor progression, inflammatory cytokines initially restrain transformation by inducing senescence, a key tumor-suppressive barrier. Here, we demonstrate that the inflammatory cytokine, oncostatin M, activates a mesenchymal/stem cell (SC) program that engages cytokine-induced senescence (CIS) in normal human epithelial cells. CIS is driven by Snail induction and requires cooperation between STAT3 and the TGFβ effector, SMAD3. Importantly, as cells escape CIS, they retain the mesenchymal/SC program and are thereby bestowed with a set of cancer SC (CSC) traits. Of therapeutic importance, cells that escape CIS can be induced back into senescence by CDK4/6 inhibition, confirming that the mechanisms allowing cells to escape senescence are targetable and reversible. Moreover, by combining CDK4/6 inhibition with a senolytic therapy, mesenchymal/CSCs can be efficiently killed. Our studies provide insight into how the CIS barriers that prevent tumorigenesis can be exploited as potential therapies for highly aggressive cancers.
These studies reveal how a normal cell's arduous escape from senescence can bestow aggressive features early in the transformation process, and how this persistent mesenchymal/SC program can create a novel potential targetability following tumor development.