Ferroptotic damage promotes pancreatic tumorigenesis through a TMEM173/STING-dependent DNA sensor pathway

Enyong Dai; Leng Han; Jiao Liu; Yangchun Xie; Herbert J Zeh; Rui Kang; Lulu Bai; Daolin Tang

doi:10.1038/s41467-020-20154-8

Ferroptotic damage promotes pancreatic tumorigenesis through a TMEM173/STING-dependent DNA sensor pathway

Nat Commun. 2020 Dec 11;11(1):6339. doi: 10.1038/s41467-020-20154-8.

Authors

Enyong Dai¹, Leng Han¹, Jiao Liu², Yangchun Xie³, Herbert J Zeh⁴, Rui Kang⁴, Lulu Bai⁵, Daolin Tang⁶

Affiliations

¹ Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130031, China.
² Protein Modification and Degradation Lab, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510120, China.
³ Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
⁴ Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
⁵ Department of Pediatric Hematology, First Hospital of Jilin University, Changchun, Jilin, 130021, China. bailulu@jlu.edu.cn.
⁶ Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA. daolin.tang@utsouthwestern.edu.

Abstract

Ferroptosis is a more recently recognized form of cell death that relies on iron-mediated oxidative damage. Here, we evaluate the impact of high-iron diets or depletion of Gpx4, an antioxidant enzyme reported as an important ferroptosis suppressor, in the pancreas of mice with cerulean- or L-arginine-induced pancreatitis, and in an oncogenic Kras murine model of spontaneous pancreatic ductal adenocarcinoma (PDAC). We find that either high-iron diets or Gpx4 depletion promotes 8-OHG release and thus activates the TMEM173/STING-dependent DNA sensor pathway, which results in macrophage infiltration and activation during Kras-driven PDAC in mice. Consequently, the administration of liproxstatin-1 (a ferroptosis inhibitor), clophosome-mediated macrophage depletion, or pharmacological and genetic inhibition of the 8-OHG-TMEM173 pathway suppresses Kras-driven pancreatic tumorigenesis in mice. GPX4 is also a prognostic marker in patients with PDAC. These findings provide pathological and mechanistic insights into ferroptotic damage in PDAC tumorigenesis in mice.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biomarkers, Tumor
Carcinogenesis / genetics
Carcinogenesis / metabolism*
Carcinoma, Pancreatic Ductal / metabolism
Carcinoma, Pancreatic Ductal / pathology
Cell Death / physiology
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism*
Cell Transformation, Neoplastic / pathology
DNA
Diet
Disease Models, Animal
Female
Ferroptosis / drug effects
Ferroptosis / physiology*
Humans
Iron / metabolism
Macrophages
Male
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice
Mice, Knockout
Pancreas / metabolism*
Pancreas / pathology
Pancreatitis / genetics
Phospholipid Hydroperoxide Glutathione Peroxidase / genetics
Phospholipid Hydroperoxide Glutathione Peroxidase / metabolism
Proto-Oncogene Proteins p21(ras) / metabolism
Quinoxalines / pharmacology
Spiro Compounds / pharmacology
Tumor Microenvironment

Substances

Biomarkers, Tumor
Membrane Proteins
Quinoxalines
Spiro Compounds
Sting1 protein, mouse
liproxstatin-1
DNA
Iron
Phospholipid Hydroperoxide Glutathione Peroxidase
glutathione peroxidase 4, mouse
Hras protein, mouse
Proto-Oncogene Proteins p21(ras)

Grants and funding

R01 CA211070/CA/NCI NIH HHS/United States