MYC-driven increases in mitochondrial DNA copy number occur early and persist throughout prostatic cancer progression

Jiayu Chen; Qizhi Zheng; Jessica L. Hicks; Levent Trabzonlu; Busra Ozbek; Tracy Jones; Ajay M. Vaghasia; Tatianna C. Larman; Rulin Wang; Mark C. Markowski; Samuel R. Denmeade; Kenneth J. Pienta; Ralph H. Hruban; Emmanuel S. Antonarakis; Anuj Gupta; Chi V. Dang; Srinivasan Yegnasubramanian; Angelo M. De Marzo

doi:10.1172/jci.insight.169868

¹Johns Hopkins University School of Medicine, Baltimore, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, United States of America

⁴Department of Urology, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Chen, J. in: JCI | PubMed | Google Scholar

¹Johns Hopkins University School of Medicine, Baltimore, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, United States of America

⁴Department of Urology, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Zheng, Q. in: JCI | PubMed | Google Scholar

¹Johns Hopkins University School of Medicine, Baltimore, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, United States of America

⁴Department of Urology, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Hicks, J. in: JCI | PubMed | Google Scholar

¹Johns Hopkins University School of Medicine, Baltimore, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, United States of America

⁴Department of Urology, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Trabzonlu, L. in: JCI | PubMed | Google Scholar |

¹Johns Hopkins University School of Medicine, Baltimore, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, United States of America

⁴Department of Urology, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Ozbek, B. in: JCI | PubMed | Google Scholar

¹Johns Hopkins University School of Medicine, Baltimore, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, United States of America

⁴Department of Urology, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Jones, T. in: JCI | PubMed | Google Scholar

¹Johns Hopkins University School of Medicine, Baltimore, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, United States of America

⁴Department of Urology, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Vaghasia, A. in: JCI | PubMed | Google Scholar

¹Johns Hopkins University School of Medicine, Baltimore, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, United States of America

⁴Department of Urology, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Larman, T. in: JCI | PubMed | Google Scholar |

¹Johns Hopkins University School of Medicine, Baltimore, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, United States of America

⁴Department of Urology, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Wang, R. in: JCI | PubMed | Google Scholar |

¹Johns Hopkins University School of Medicine, Baltimore, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, United States of America

⁴Department of Urology, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Markowski, M. in: JCI | PubMed | Google Scholar

¹Johns Hopkins University School of Medicine, Baltimore, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, United States of America

⁴Department of Urology, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Denmeade, S. in: JCI | PubMed | Google Scholar

¹Johns Hopkins University School of Medicine, Baltimore, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, United States of America

⁴Department of Urology, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Pienta, K. in: JCI | PubMed | Google Scholar |

¹Johns Hopkins University School of Medicine, Baltimore, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, United States of America

⁴Department of Urology, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Hruban, R. in: JCI | PubMed | Google Scholar |

¹Johns Hopkins University School of Medicine, Baltimore, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, United States of America

⁴Department of Urology, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Antonarakis, E. in: JCI | PubMed | Google Scholar |

¹Johns Hopkins University School of Medicine, Baltimore, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, United States of America

⁴Department of Urology, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Gupta, A. in: JCI | PubMed | Google Scholar

¹Johns Hopkins University School of Medicine, Baltimore, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, United States of America

⁴Department of Urology, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Dang, C. in: JCI | PubMed | Google Scholar

¹Johns Hopkins University School of Medicine, Baltimore, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, United States of America

⁴Department of Urology, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Yegnasubramanian, S. in: JCI | PubMed | Google Scholar |

¹Johns Hopkins University School of Medicine, Baltimore, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, United States of America

⁴Department of Urology, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by De Marzo, A. in: JCI | PubMed | Google Scholar |

JCI Insight. https://doi.org/10.1172/jci.insight.169868.
Copyright © 2023, Chen et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published November 16, 2023 - Version history

Increased mitochondrial function may render some cancers vulnerable to mitochondrial inhibitors. Since mitochondrial function is regulated partly by mitochondrial DNA copy number (mtDNAcn), accurate measurements of mtDNAcn could help reveal which cancers are driven by increased mitochondrial function and may be candidates for mitochondrial inhibition. However, prior studies have employed bulk macrodissections that fail to account for cell type-specific or tumor cell heterogeneity in mtDNAcn. These studies have often produced unclear results, particularly in prostate cancer. Herein, we developed a multiplex in situ method to spatially quantify cell type specific mtDNAcn. We show that mtDNAcn is increased in luminal cells of high-grade prostatic intraepithelial neoplasia (HGPIN), is increased in prostatic adenocarcinomas (PCa), and is further elevated in metastatic castration-resistant prostate cancer. Increased PCa mtDNAcn was validated by two orthogonal methods and is accompanied by increases in mtRNAs and enzymatic activity. Mechanistically, MYC inhibition in prostate cancer cells decreases mtDNA replication and expression of several mtDNA replication genes, and MYC activation in the mouse prostate leads to increased mtDNA levels in the neoplastic prostate cells. Our in situ approach also revealed elevated mtDNAcn in precancerous lesions of the pancreas and colon/rectum, demonstrating generalization across cancer types using clinical tissue samples.

Version 1 (November 16, 2023): In-Press Preview

MYC-driven increases in mitochondrial DNA copy number occur early and persist throughout prostatic cancer progression

Article tools

Metrics

Go to

MYC-driven increases in mitochondrial DNA copy number occur early and persist throughout prostatic cancer progression

Article tools

Metrics

Go to

Sign up for email alerts