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

• Published in: Cancer cell Vol. 17; no. 3; pp. 262 - 272
• Main Authors: Reimann, Maurice, Lee, Soyoung, Loddenkemper, Christoph, Doerr, Jan R, Tabor, Vedrana, Aichele, Peter, Stein, Harald, Doerken, Bernd, Jenuwein, Thomas, Schmitt, Clemens A
• Format: Journal Article
• Language: English
• Published: 16.03.2010
• ISSN: 1535-6108
• DOI: 10.1016/j.ccr.2009.12.043

Activated 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 EI14-myc transgenic mouse lymphoma model, we show here inaavivo that apoptotic lymphoma cells activate macrophages to secrete transforming growth factor b (TGF-b) as a critical non-cell-autonomous inducer of cellular senescence. Accordingly, neutralization of TGF-b 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. Display Omitted a-[ordm Myc drives tumor-limiting senescence via cell-autonomous and non-cell-autonomous ways a-[ordm The histone methyltransferase Suv39h1 is essential for Myc-induced senescence a-[ordm Apoptotic body-engulfing macrophages secrete TGF-b that induces tumor senescence a-[ordm These tumor/host interactions were recapitulated in human aggressive B cell lymphomas