The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1.

The senescence-associated secretory phenotype (SASP) can be provoked by side effects of therapeutic agents, fueling advanced complications including cancer resistance. However, the intracellular signal network supporting initiation and development of the SASP driven by treatment-induced damage remains unclear. Here we report that the transcription factor Zscan4 is elevated for expression by an ATM-TRAF6-TAK1 axis during the acute DNA damage response and enables a long term SASP in human stromal cells. Further, TAK1 activates p38 and PI3K/Akt/mTOR to support the persistent SASP signaling. As TAK1 is implicated in dual feedforward mechanisms to orchestrate the SASP development, pharmacologically targeting TAK1 deprives cancer cells of resistance acquired from treatment-damaged stromal cells in vitro and substantially promotes tumour regression in vivo. Together, our study reveals a novel network that links functionally critical molecules associated with the SASP development in therapeutic settings, thus opening new avenues to improve clinical outcomes and advance precision medicine.