Tumor stroma-derived TGF-beta limits myc-driven lymphomagenesis via Suv39h1-dependent senescence.
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 Emu-myc transgenic mouse lymphoma model, we show here in vivo that apoptotic lymphoma cells activate macrophages to secrete transforming growth factor beta (TGF-beta) as a critical non-cell-autonomous inducer of cellular senescence. Accordingly, neutralization of TGF-beta 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.
Reimann
Maurice
M
Charité - Universitätsmedizin Berlin/Molekulares Krebsforschungszentrum der Charité - MKFZ, 13353 Berlin, Germany.
Lee
Soyoung
S
Loddenkemper
Christoph
C
Dörr
Jan R
JR
Tabor
Vedrana
V
Aichele
Peter
P
Stein
Harald
H
Dörken
Bernd
B
Jenuwein
Thomas
T
Schmitt
Clemens A
CA
D000818:Animals; D017209:Apoptosis; D016922:Cellular Senescence / Q000502:physiology*; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism; D008780:Methyltransferases / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism* / Q000502:physiology; D012097:Repressor Proteins / Q000378:metabolism* / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; C498700:Suv39h1 protein, mouse; D008780:Methyltransferases