Tumor Stroma-Derived TGF-β Limits Myc-Driven Lymphomagenesis via Suv39h1-Dependent Senescence

Summary ted RAS/BRAF oncogenes induce cellular senescence as a tumor-suppressive barrier in early cancer development, at least in part, via an oncogene-evoked DNA damage response (DDR). In contrast, Myc activation—although producing a DDR as well—is known to primarily elicit an apoptotic countermeasure. Using the Eμ-myc transgenic mouse lymphoma model, we show here in vivo that apoptotic lymphoma cells activate macrophages to secrete transforming growth factor β (TGF-β) as a critical non-cell-autonomous inducer of cellular senescence. Accordingly, neutralization of TGF-β action, like genetic inactivation of the senescence-related histone methyltransferase Suv39h1, significantly accelerates Myc-driven tumor development via cancellation of cellular senescence. These findings, recapitulated in human aggressive B cell lymphomas, demonstrate that tumor-prompted stroma-derived signals may limit tumorigenesis by feedback senescence induction.