p38MAPK Plays a Crucial Role in Stromal-Mediated Tumorigenesis

Abstract

Neoplastic cells rely on the tumor microenvironment (TME) for survival and progression factors. Indeed, senescent and cancer-associated fibroblasts (CAFs) express factors that promote tumorigenesis that are collectively referred to as the senescence-associated secretory phenotype (SASP). Despite their importance in tumorigenesis, the mechanisms that control TME-derived factor expression remain poorly understood. Here we address a key unanswered question, how the SASP is sustained in senescent fibroblasts and CAFs. We find that the mitogen-activated protein kinase p38 (p38MAPK) controls AUF1 occupancy on SASP mRNAs and thus controls their stability. The importance of this regulatory mechanism is underscored by our findings that stromal-specific p38MAPK inhibition abrogates the tumor-promoting activities of CAFs and senescent fibroblasts. Our data suggest that targeting SASP mRNA stability through inhibition of p38MAPK will significantly aid the development of clinical strategies to target the TME.

Soil Amendments That Slow Cancer Growth

“…Consistent with this notion, Alspach and colleagues ( 8 ) show that the stroma of breast cancer is enriched in SASP proteins. These promising data underscore a gap in the study in that the functional demonstration relies exclusively on cancer cell lines.…”

“…The new study by Alspach and colleagues ( 8 ) in this issue describes a posttranscriptional mechanism mediated by p38MAPK activity on AUF1 to stabilize SASP mRNA species common to both CAFs and senescent fi broblasts (Fig. 1).…”

“…A key feature of the study by Alspach and colleagues ( 8 ) is to provide a link between p38MAPK, AUF1, and the posttranscription regulation of key SASP components, such as IL6 and IL8, in CAFs and senescent fi broblasts. Crucially , they then provide strong data from models demonstrating that targeting p38MAPK in the stroma both inhibits the development of tumor growth and attenuates the growth of established tumors, thus highlighting p38MAPK as a potentially relevant target.…”

Oncogenic Ras modulates p38 MAPK-mediated inflammatory cytokine production in glioblastoma cells

“…p38 MAPK function in diverse inflammatory diseases is well defined. [30][31][32] In cancer, p38 MAPK regulates DNA damage response, 33 oncogene-induced senescence, 34 senescence-associated secretory phenotype, 23,35 stromal-mediated tumorigenesis 36 and mitotic cell cycle progression. 37 We have previously shown that p38 MAPK drives microglia-derived inflammation 17 and is the convergent pathway of EGFRvIII and IL-1b signaling in glioblastoma cellderived inflammation.…”

RNA-binding Protein Immunoprecipitation (RIP) to Examine AUF1 Binding to Senescence-Associated Secretory Phenotype (SASP) Factor mRNA

“…Here, we describe the immunoprecipitation of the RNA-binding protein AUF1 with several different factors associated with the senescence-associated secretory phenotype (SASP) (Alspach and Stewart, 2013), specifically IL6 and IL8. This protocol was originally published in Alspach et al (2014). …”