title: Fibulin-5 Blocks Microenvironmental ROS in Pancreatic Cancer.
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.
authors.affiliation: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas.
authors.forename: Miao
authors.initials: M
authors.lastname: Wang
authors.affiliation: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas.
authors.forename: Mary
authors.initials: M
authors.lastname: Topalovski
authors.affiliation: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Toombs
authors.affiliation: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Wright
authors.affiliation: Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Moore
authors.affiliation: Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.
authors.forename: David A
authors.initials: DA
authors.lastname: Boothman
authors.affiliation: Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yanagisawa
authors.affiliation: Department of Pathology, UT MD Anderson Cancer Center, Houston, Texas.
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, Dallas, Texas.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Witkiewicz
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, Dallas, Texas.
authors.forename: Diego H
authors.initials: DH
authors.lastname: Castrillon
authors.affiliation: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas. Department of Surgery, UT Southwestern Medical Center, Dallas, Texas. Department of Pharmacology, UT Southwestern Medical Center, Dallas, Texas. rolf.brekken@utsouthwestern.edu.
authors.forename: Rolf A
authors.initials: RA
authors.lastname: Brekken
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000502:physiology
chemical_list: D016326:Extracellular Matrix Proteins; C492373:FBLN5 protein, human; C120769:Fbln5 protein, mouse; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins