
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.09.09.611245
preprint
1
Article
Three-dimensional analysis of mitochondria in a patient-derived xenograft model of triple negative breast cancer reveals mitochondrial network remodeling following chemotherapy treatments
Berner Mariah J. http://orcid.org/0000-0001-7950-8728

Beasley Heather K. http://orcid.org/0000-0002-4636-2889

Vue Zer http://orcid.org/0000-0002-3502-8906

Lane Audra http://orcid.org/0009-0008-6911-8572

Vang Larry http://orcid.org/0000-0001-9098-3650

Baek Mokryun L. http://orcid.org/0000-0001-5288-3173

Marshall Andrea G. http://orcid.org/0000-0001-9997-4478

Killion Mason http://orcid.org/0009-0008-0874-9979

Zeleke Faben
Shao Bryanna
Parker Dominque
Peterson Autumn
Rhoades Julie Sterling
Scudese Estevão
Dobrolecki Lacey E. http://orcid.org/0000-0001-6839-629X

Lewis Michael T.
Hinton Antentor http://orcid.org/0000-0002-7730-952X

Echeverria Gloria V. http://orcid.org/0000-0002-3772-9298

09 9 2024
2024.09.09.611245https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.09.09.611245
nihpp-2024.09.09.611245.pdf
ABSTRACT

Mitochondria are hubs of metabolism and signaling and play an important role in tumorigenesis, therapeutic resistance, and metastasis in many cancer types. Various laboratory models of cancer demonstrate the extraordinary dynamics of mitochondrial structure, but little is known about the role of mitochondrial structure in resistance to anticancer therapy. We previously demonstrated the importance of mitochondrial structure and oxidative phosphorylation in the survival of chemotherapy-refractory triple negative breast cancer (TNBC) cells. As TNBC is a highly aggressive breast cancer subtype with few targeted therapy options, conventional chemotherapies remain the backbone of early TNBC treatment. Unfortunately, approximately 45% of TNBC patients retain substantial residual tumor burden following chemotherapy, associated with abysmal prognoses. Using an orthotopic patient-derived xenograft mouse model of human TNBC, we compared mitochondrial structures between treatment-naïve tumors and residual tumors after conventional chemotherapeutics were administered singly or in combination. We reconstructed 1,750 mitochondria in three dimensions from serial block-face scanning electron micrographs, providing unprecedented insights into the complexity and intra-tumoral heterogeneity of mitochondria in TNBC. Following exposure to carboplatin or docetaxel given individually, residual tumor mitochondria exhibited significant increases in mitochondrial complexity index, area, volume, perimeter, width, and length relative to treatment-naïve tumor mitochondria. In contrast, residual tumors exposed to those chemotherapies given in combination exhibited diminished mitochondrial structure changes. Further, we document extensive intra-tumoral heterogeneity of mitochondrial structure, especially prior to chemotherapeutic exposure. These results highlight the potential for structure-based monitoring of chemotherapeutic responses and reveal potential molecular mechanisms that underlie chemotherapeutic resistance in TNBC.
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pmc
