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 journalArticle

18 Citations (Scopus)

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

Fingerprint

Pancreatic Neoplasms
Reactive Oxygen Species
Integrins
Adenocarcinoma
Neoplasms
Oxidative Stress
Fibronectins
Cell Communication
Antineoplastic Agents
Extracellular Matrix
fibulin
Cell Survival
Homeostasis
Mutation
Growth
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Fibulin-5 blocks microenvironmental ROS in pancreatic cancer. / Wang, Miao; Topalovski, Mary; Toombs, Jason E.; Wright, Christopher M.; Moore, Zachary R.; Boothman, David A.; Yanagisawa, Hiromi; Wang, Huamin; Witkiewicz, Agnieszka; Castrillon, Diego H.; Brekken, Rolf A.

In: Cancer Research, Vol. 75, No. 23, 01.12.2015, p. 5058-5069.

Research output: Contribution to journalArticle

Wang, M, Topalovski, M, Toombs, JE, Wright, CM, Moore, ZR, Boothman, DA, Yanagisawa, H, Wang, H, Witkiewicz, A, Castrillon, DH & Brekken, RA 2015, 'Fibulin-5 blocks microenvironmental ROS in pancreatic cancer', Cancer Research, vol. 75, no. 23, pp. 5058-5069. https://doi.org/10.1158/0008-5472.CAN-15-0744
Wang M, Topalovski M, Toombs JE, Wright CM, Moore ZR, Boothman DA et al. Fibulin-5 blocks microenvironmental ROS in pancreatic cancer. Cancer Research. 2015 Dec 1;75(23):5058-5069. https://doi.org/10.1158/0008-5472.CAN-15-0744
Wang, Miao ; Topalovski, Mary ; Toombs, Jason E. ; Wright, Christopher M. ; Moore, Zachary R. ; Boothman, David A. ; Yanagisawa, Hiromi ; Wang, Huamin ; Witkiewicz, Agnieszka ; Castrillon, Diego H. ; Brekken, Rolf A. / Fibulin-5 blocks microenvironmental ROS in pancreatic cancer. In: Cancer Research. 2015 ; Vol. 75, No. 23. pp. 5058-5069.
@article{ec999de9621f4c9c93244ef3156afc97,
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.",
author = "Miao Wang and Mary Topalovski and Toombs, {Jason E.} and Wright, {Christopher M.} and Moore, {Zachary R.} and Boothman, {David A.} and Hiromi Yanagisawa and Huamin Wang and Agnieszka Witkiewicz and Castrillon, {Diego H.} and Brekken, {Rolf A.}",
year = "2015",
month = "12",
day = "1",
doi = "10.1158/0008-5472.CAN-15-0744",
language = "English (US)",
volume = "75",
pages = "5058--5069",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "23",

}

TY - JOUR

T1 - Fibulin-5 blocks microenvironmental ROS in pancreatic cancer

AU - Wang, Miao

AU - Topalovski, Mary

AU - Toombs, Jason E.

AU - Wright, Christopher M.

AU - Moore, Zachary R.

AU - Boothman, David A.

AU - Yanagisawa, Hiromi

AU - Wang, Huamin

AU - Witkiewicz, Agnieszka

AU - Castrillon, Diego H.

AU - Brekken, Rolf A.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84955476499&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84955476499&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-15-0744

DO - 10.1158/0008-5472.CAN-15-0744

M3 - Article

VL - 75

SP - 5058

EP - 5069

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 23

ER -