P38MAPK plays a crucial role in stromal-mediated tumorigenesis

Elise Alspach, Kevin C. Flanagan, Xianmin Luo, Megan K. Ruhland, Hui Huang, Ermira Pazolli, Maureen J. Donlin, Timothy Marsh, David Piwnica-Worms, Joseph Monahan, Deborah V. Novack, Sandra S. McAllister, Sheila A. Stewart

Research output: Contribution to journalArticlepeer-review

106 Scopus citations


Neoplastic cells rely on the tumor microenvironment (TME) for survival and progression factors. Indeed, senescent and cancer-associated fibroblasts (CAF) 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 stromalspecific 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. SIGNIFICANCE: The TME plays a key role in tumorigenesis. We demonstrate that p38MAPK governs a posttranscriptional mechanism that sustains the protumorigenic SASP. Inhibition of p38MAPK abrogates the tumor-promoting activities of CAFs and senescent fibroblasts. Thus, p38MAPK is a TME-specific Achilles' heel that may be exploited as a new therapeutic target.

Original languageEnglish (US)
Pages (from-to)716-729
Number of pages14
JournalCancer discovery
Issue number6
StatePublished - Jun 2014
Externally publishedYes

ASJC Scopus subject areas

  • Oncology


Dive into the research topics of 'P38MAPK plays a crucial role in stromal-mediated tumorigenesis'. Together they form a unique fingerprint.

Cite this