Enhanced mitochondrial fission suppresses signaling and metastasis in triple-negative breast cancer

Brock A. Humphries; Alyssa C. Cutter; Johanna M. Buschhaus; Yu-Chih Chen; Tonela Qyli; Dilrukshika S. W. Palagama; Samantha Eckley; Tanner H. Robison; Avinash Bevoor; Benjamin Chiang; Henry R. Haley; Saswat Sahoo; Phillip C. Spinosa; Dylan B. Neale; Jagadish Boppisetti; Debashis Sahoo; Pradipta Ghosh; Joerg Lahann; Brian D. Ross; Eusik Yoon; Kathryn E. Luker; Gary D. Luker

doi:10.1186/s13058-020-01301-x

Breast Cancer Research (Jun 2020)

Enhanced mitochondrial fission suppresses signaling and metastasis in triple-negative breast cancer

Brock A. Humphries,
Alyssa C. Cutter,
Johanna M. Buschhaus,
Yu-Chih Chen,
Tonela Qyli,
Dilrukshika S. W. Palagama,
Samantha Eckley,
Tanner H. Robison,
Avinash Bevoor,
Benjamin Chiang,
Henry R. Haley,
Saswat Sahoo,
Phillip C. Spinosa,
Dylan B. Neale,
Jagadish Boppisetti,
Debashis Sahoo,
Pradipta Ghosh,
Joerg Lahann,
Brian D. Ross,
Eusik Yoon,
Kathryn E. Luker,
Gary D. Luker

Affiliations

Brock A. Humphries: Center for Molecular Imaging, Department of Radiology, University of Michigan
Alyssa C. Cutter: Center for Molecular Imaging, Department of Radiology, University of Michigan
Johanna M. Buschhaus: Center for Molecular Imaging, Department of Radiology, University of Michigan
Yu-Chih Chen: Department of Electrical Engineering and Computer Science, University of Michigan
Tonela Qyli: Center for Molecular Imaging, Department of Radiology, University of Michigan
Dilrukshika S. W. Palagama: Center for Molecular Imaging, Department of Radiology, University of Michigan
Samantha Eckley: Unit for Laboratory Medicine, University of Michigan
Tanner H. Robison: Center for Molecular Imaging, Department of Radiology, University of Michigan
Avinash Bevoor: Center for Molecular Imaging, Department of Radiology, University of Michigan
Benjamin Chiang: Center for Molecular Imaging, Department of Radiology, University of Michigan
Henry R. Haley: Center for Molecular Imaging, Department of Radiology, University of Michigan
Saswat Sahoo: Department of Electrical Engineering and Computer Science, University of Michigan
Phillip C. Spinosa: Department of Chemical Engineering, University of Michigan
Dylan B. Neale: Department of Chemical Engineering, University of Michigan
Jagadish Boppisetti: Center for Molecular Imaging, Department of Radiology, University of Michigan
Debashis Sahoo: Department of Pediatrics, Department of Computer Science and Engineering, Jacob’s School of Engineering, Rebecca and John Moore Comprehensive Cancer Center, University of California San Diego
Pradipta Ghosh: Department of Medicine, Department of Cellular and Molecular Medicine, Rebecca and John Moore Comprehensive Cancer Center, Veterans Affairs Medical Center, University of California San Diego
Joerg Lahann: Biointerfaces Institute, Departments of Chemical Engineering, Materials Science and Engineering, Biomedical Engineering, and Macromolecular Science and Engineering, University of Michigan
Brian D. Ross: Center for Molecular Imaging, Department of Radiology, University of Michigan
Eusik Yoon: Department of Biomedical Engineering, University of Michigan
Kathryn E. Luker: Center for Molecular Imaging, Department of Radiology, University of Michigan
Gary D. Luker: Center for Molecular Imaging, Department of Radiology, University of Michigan

DOI: https://doi.org/10.1186/s13058-020-01301-x
Journal volume & issue: Vol. 22, no. 1
pp. 1 – 18

Abstract

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Abstract Background Mitochondrial dynamics underlies malignant transformation, cancer progression, and response to treatment. Current research presents conflicting evidence for functions of mitochondrial fission and fusion in tumor progression. Here, we investigated how mitochondrial fission and fusion states regulate underlying processes of cancer progression and metastasis in triple-negative breast cancer (TNBC). Methods We enforced mitochondrial fission and fusion states through chemical or genetic approaches and measured migration and invasion of TNBC cells in 2D and 3D in vitro models. We also utilized kinase translocation reporters (KTRs) to identify single cell effects of mitochondrial state on signaling cascades, PI3K/Akt/mTOR and Ras/Raf/MEK/ERK, commonly activated in TNBC. Furthermore, we determined effects of fission and fusion states on metastasis, bone destruction, and signaling in mouse models of breast cancer. Results Enforcing mitochondrial fission through chemical or genetic approaches inhibited migration, invasion, and metastasis in TNBC. Breast cancer cells with predominantly fissioned mitochondria exhibited reduced activation of Akt and ERK both in vitro and in mouse models of breast cancer. Treatment with leflunomide, a potent activator of mitochondrial fusion proteins, overcame inhibitory effects of fission on migration, signaling, and metastasis. Mining existing datasets for breast cancer revealed that increased expression of genes associated with mitochondrial fission correlated with improved survival in human breast cancer. Conclusions In TNBC, mitochondrial fission inhibits cellular processes and signaling pathways associated with cancer progression and metastasis. These data suggest that therapies driving mitochondrial fission may benefit patients with breast cancer.

Published in Breast Cancer Research

ISSN: 1465-5411 (Print); 1465-542X (Online)
Publisher: BMC
Country of publisher: United Kingdom
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://breast-cancer-research.biomedcentral.com/

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