DNA Damage-Mediated Induction of a Chemoresistant Niche

SummaryWhile numerous cell-intrinsic processes are known to play decisive roles in chemotherapeutic response, relatively little is known about the impact of the tumor microenvironment on therapeutic outcome. Here, we use a well-established mouse model of Burkitt's lymphoma to show that paracrine factors in the tumor microenvironment modulate lymphoma cell survival following the administration of genotoxic chemotherapy. Specifically, IL-6 and Timp-1 are released in the thymus in response to DNA damage, creating a “chemo-resistant niche” that promotes the survival of a minimal residual tumor burden and serves as a reservoir for eventual tumor relapse. Notably, IL-6 is released acutely from thymic endothelial cells in a p38-dependent manner following genotoxic stress, and this acute secretory response precedes the gradual induction of senescence in tumor-associated stromal cells. Thus, conventional chemotherapies can induce tumor regression while simultaneously eliciting stress responses that protect subsets of tumor cells in select anatomical locations from drug action.PaperFlick To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon belowHelp with MP4 filesOptionsDownload video (17520 K)

Graphical AbstractFigure optionsDownload high-quality image (272 K)Download as PowerPoint slideHighlights
► Lymphoma cells in the thymus are protected from genotoxic chemotherapy
► DNA damage induces an acute p38-dependent release of prosurvival factors
► Paracrine signaling by IL-6 and Timp1 leads to survival of a residual tumor burden
► Inhibition of cytokine-induced signaling potentiates chemotherapeutic efficacy