Fibulin-5 blocks microenvironmental ROS in pancreatic cancer

Miao Wang, Mary Topalovski, Jason E. Toombs, Christopher M. Wright, Zachary R. Moore, David A. Boothman, Hiromi Yanagisawa, Huamin Wang, Agnieszka Witkiewicz, Diego H. Castrillon, Rolf A. Brekken

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Elevated oxidative stress is an aberration seen in many solid tumors, and exploiting this biochemical difference has the potential to enhance the efficacy of anticancer agents. Homeostasis of reactive oxygen species (ROS) is important for normal cell function, but excessive production of ROS can result in cellular toxicity, and therefore ROS levels must be balanced finely. Here, we highlight the relationship between the extracellular matrix and ROS production by reporting a novel function of the matricellular protein Fibulin-5 (Fbln5). We used genetically engineered mouse models of pancreatic ductal adenocarcinoma (PDAC) and found that mutation of the integrin-binding domain of Fbln5 led to decreased tumor growth, increased survival, and enhanced chemoresponse to standard PDAC therapies. Through mechanistic investigations, we found that improved survival was due to increased levels of oxidative stress in Fbln5-mutant tumors. Furthermore, loss of the Fbln5-integrin interaction augmented fibronectin signaling, driving integrin-induced ROS production in a 5-lipooxygenase-dependent manner. These data indicate that Fbln5 promotes PDAC progression by functioning as a molecular rheostat that modulates cell-ECM interactions to reduce ROS production, and thus tip the balance in favor of tumor cell survival and treatment-refractory disease.

Original languageEnglish (US)
Pages (from-to)5058-5069
Number of pages12
JournalCancer research
Volume75
Issue number23
DOIs
StatePublished - Dec 1 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Fibulin-5 blocks microenvironmental ROS in pancreatic cancer'. Together they form a unique fingerprint.

Cite this