Intercellular Mitochondrial Transfer Contributes to Microenvironmental Redirection of Cancer Cell Fate

Authors

Julie Sofie Bjerring, Macon & Joan Brock Virginia Health Sciences at Old Dominion UniversityFollow
Yara Khodour, Macon & Joan Brock Virginia Health Sciences at Old Dominion UniversityFollow
Emilee Anne Peterson, Macon & Joan Brock Virginia Health Sciences at Old Dominion UniversityFollow
Patrick Christian Sachs, Macon & Joan Brock Virginia Health Sciences at Old Dominion UniversityFollow
Robert David Bruno, Macon & Joan Brock Virginia Health SciencesFollow

Document Type

Article

Publication Date

2025

DOI

10.1111/febs.70002

Publication Title

FEBS Journal

Volume

Article in Press

Pages

17 pp.

Abstract

The mammary microenvironment has been shown to suppress tumor progression by redirecting cancer cells to adopt a normal mammary epithelial progenitor fate in vivo. However, the mechanism(s) by which this alteration occurs has yet to be defined. Here, we test the hypothesis that mitochondrial transfer from normal mammary epithelial cells to breast cancer cells plays a role in this redirection process. We evaluate mitochondrial transfer in 2D and 3D organoids using our unique 3D bioprinting system to produce chimeric organoids containing normal and cancer cells. We demonstrate that breast cancer tumoroid growth is hindered following interaction with mammary epithelial cells in both 2D and 3D environments. Furthermore, we show mitochondrial transfer occurs between donor mammary epithelial cells and recipient cancer cells primarily through tunneling nanotubes (TNTs) with minimal amounts seen from extracellular transfer of mitochondria, likely via extracellular vesicles (EVs). This organelle exchange results in various cellular and metabolic alterations within cancer cells, reducing their proliferative potential, and making them susceptible to microenvironmental control. Our results demonstrate that mitochondrial transfer contributes to microenvironmental redirection of cancer cells through alteration of metabolic and molecular functions of the recipient cancer cells. To the best of our knowledge, this is the first description of a 3D bioprinter-assisted organoid system for studying mitochondrial transfer. These studies are also the first mechanistic insights into the process of mammary microenvironmental redirection of cancer and provide a framework for new therapeutic strategies to control cancer.

Rights

© 2025 The Authors.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Data Availability

Article states: "The data that support the findings of this study are available from the corresponding authors [rbruno@odu.edu; psachs@odu.edu] upon reasonable request."

ORCID

0009-0008-5556-298X (Bjerring), 0000-0002-6728-6627 (Khodour), 0000-0002-0871-6789 (Sachs), 0000-0003-3329-9478 (Bruno)

Original Publication Citation

Bjerring, J. S., Khodour, Y., Peterson, E. A., Sachs, P. C., & Bruno, R. D. (2025). Intercellular mitochondrial transfer contributes to microenvironmental redirection of cancer cell fate. FEBS Journal. Advance online publication. https://doi.org/10.1111/febs.70002

Repository Citation

Bjerring, Julie Sofie; Khodour, Yara; Peterson, Emilee Anne; Sachs, Patrick Christian; and Bruno, Robert David, "Intercellular Mitochondrial Transfer Contributes to Microenvironmental Redirection of Cancer Cell Fate" (2025). School of Medical Diagnostics & Translational Sciences Faculty Publications. 45.
https://digitalcommons.odu.edu/medicaldiagnostics_fac_pubs/45