Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1

Yun Zhao; Zhongshun Liu; Guoqiang Liu; Yuting Zhang; Sheng Liu; Dailin Gan; Wennan Chang; Xiaoxia Peng; Eun Suh Sung; Keegan Gilbert; Yini Zhu; Xuechun Wang; Ziyu Zeng; Hope Baldwin; Guanzhu Ren; Jessica Weaver; Anna Huron; Toni Mayberry; Qingfei Wang; Yujue Wang; Maria Elena Diaz-Rubio; Xiaoyang Su; M Sharon Stack; Siyuan Zhang; Xuemin Lu; Ryan D Sheldon; Jun Li; Chi Zhang; Jun Wan; Xin Lu

doi:10.1016/j.cmet.2023.09.004

Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1

Cell Metab. 2023 Oct 3;35(10):1688-1703.e10. doi: 10.1016/j.cmet.2023.09.004.

Authors

Yun Zhao¹, Zhongshun Liu¹, Guoqiang Liu², Yuting Zhang², Sheng Liu³, Dailin Gan⁴, Wennan Chang⁵, Xiaoxia Peng¹, Eun Suh Sung¹, Keegan Gilbert¹, Yini Zhu², Xuechun Wang¹, Ziyu Zeng¹, Hope Baldwin¹, Guanzhu Ren¹, Jessica Weaver¹, Anna Huron¹, Toni Mayberry⁶, Qingfei Wang⁷, Yujue Wang⁸, Maria Elena Diaz-Rubio⁸, Xiaoyang Su⁹, M Sharon Stack¹⁰, Siyuan Zhang¹¹, Xuemin Lu¹, Ryan D Sheldon¹², Jun Li⁴, Chi Zhang⁵, Jun Wan¹³, Xin Lu¹⁴

Affiliations

¹ Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA.
² Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA; Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, IN 46556, USA.
³ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
⁴ Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, IN 46556, USA.
⁵ Department of Medical and Molecular Genetics and Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Electrical and Computer Engineering, Purdue University, Indianapolis, IN 46202, USA.
⁶ Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA.
⁷ Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
⁸ Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA.
⁹ Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA; Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
¹⁰ Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA; Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
¹¹ Department of Pathology, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
¹² Mass Spectrometry Core, Van Andel Institute, Grand Rapids, MI, USA.
¹³ Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, IN 46556, USA; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; School of Informatics and Computing, Indiana University - Purdue University at Indianapolis, Indianapolis, IN 46202, USA.
¹⁴ Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA; Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, IN 46556, USA; Tumor Microenvironment and Metastasis Program, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA. Electronic address: xlu@nd.edu.

PMID: 37793345
PMCID: PMC10558089 (available on 2024-10-03)
DOI: 10.1016/j.cmet.2023.09.004

Abstract

Metastasis causes breast cancer-related mortality. Tumor-infiltrating neutrophils (TINs) inflict immunosuppression and promote metastasis. Therapeutic debilitation of TINs may enhance immunotherapy, yet it remains a challenge to identify therapeutic targets highly expressed and functionally essential in TINs but under-expressed in extra-tumoral neutrophils. Here, using single-cell RNA sequencing to compare TINs and circulating neutrophils in murine mammary tumor models, we identified aconitate decarboxylase 1 (Acod1) as the most upregulated metabolic enzyme in mouse TINs and validated high Acod1 expression in human TINs. Activated through the GM-CSF-JAK/STAT5-C/EBPβ pathway, Acod1 produces itaconate, which mediates Nrf2-dependent defense against ferroptosis and upholds the persistence of TINs. Acod1 ablation abates TIN infiltration, constrains metastasis (but not primary tumors), bolsters antitumor T cell immunity, and boosts the efficacy of immune checkpoint blockade. Our findings reveal how TINs escape from ferroptosis through the Acod1-dependent immunometabolism switch and establish Acod1 as a target to offset immunosuppression and improve immunotherapy against metastasis.

Keywords: Acod1; MDSC; breast cancer; ferroptosis; immune checkpoint blockade; immune metabolism; itaconate; metastasis; neutrophil; single-cell RNA sequencing.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Breast Neoplasms* / metabolism
Carboxy-Lyases* / metabolism
Female
Ferroptosis*
Humans
Melanoma, Cutaneous Malignant
Mice
Neutrophils

Substances

aconitate decarboxylase
Carboxy-Lyases

Abstract

Publication types

MeSH terms

Substances

Grants and funding