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Mitochondrial structure and function adaptation in residual triple negative breast cancer cells surviving chemotherapy treatment

Oncogene volume 42, pages 1117–1131 (2023)Cite this article

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Abstract

Neoadjuvant chemotherapy (NACT) used for triple negative breast cancer (TNBC) eradicates tumors in ~45% of patients. Unfortunately, TNBC patients with substantial residual cancer burden have poor metastasis free and overall survival rates. We previously demonstrated mitochondrial oxidative phosphorylation (OXPHOS) was elevated and was a unique therapeutic dependency of residual TNBC cells surviving NACT. We sought to investigate the mechanism underlying this enhanced reliance on mitochondrial metabolism. Mitochondria are morphologically plastic organelles that cycle between fission and fusion to maintain mitochondrial integrity and metabolic homeostasis. The functional impact of mitochondrial structure on metabolic output is highly context dependent. Several chemotherapy agents are conventionally used for neoadjuvant treatment of TNBC patients. Upon comparing mitochondrial effects of conventional chemotherapies, we found that DNA-damaging agents increased mitochondrial elongation, mitochondrial content, flux of glucose through the TCA cycle, and OXPHOS, whereas taxanes instead decreased mitochondrial elongation and OXPHOS. The mitochondrial effects of DNA-damaging chemotherapies were dependent on the mitochondrial inner membrane fusion protein optic atrophy 1 (OPA1). Further, we observed heightened OXPHOS, OPA1 protein levels, and mitochondrial elongation in an orthotopic patient-derived xenograft (PDX) model of residual TNBC. Pharmacologic or genetic disruption of mitochondrial fusion and fission resulted in decreased or increased OXPHOS, respectively, revealing longer mitochondria favor oxphos in TNBC cells. Using TNBC cell lines and an in vivo PDX model of residual TNBC, we found that sequential treatment with DNA-damaging chemotherapy, thus inducing mitochondrial fusion and OXPHOS, followed by MYLS22, a specific inhibitor of OPA1, was able to suppress mitochondrial fusion and OXPHOS and significantly inhibit regrowth of residual tumor cells. Our data suggest that TNBC mitochondria can optimize OXPHOS through OPA1-mediated mitochondrial fusion. These findings may provide an opportunity to overcome mitochondrial adaptations of chemoresistant TNBC.

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Fig. 1: Conventional chemotherapies differentially alter mitochondrial metabolism in TNBC cells.
Fig. 2: Mitochondrial structure is altered in residual TNBC cells surviving conventional chemotherapy treatments.
Fig. 3: Pharmacologic perturbation of mitochondrial morphology alters mitochondrial metabolism in TNBC cells.
Fig. 4: Genetic perturbation of mitochondrial morphology alters mitochondrial metabolism in TNBC cells.
Fig. 5: Mitochondrial morphology impacts chemo-sensitivity of TNBC cells.
Fig. 6: Mitochondrial adaptations in a PDX model of post-AC residual TNBC.
Fig. 7: Pharmacologic inhibition of OPA1 slows residual tumor regrowth in a PDX model.

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The authors confirm that the data supporting the findings of this study are available within the paper and its supplementary materials.

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Acknowledgements

We are grateful to the breast cancer patients who donated their biopsies for cell lines and PDX models. Ms Janice Cowden and Mr Joshua Newby provided research advocacy support for this work. Dr Helen Piwnica-Worms provided the PIM001-P PDX model. The generation of PIM001-P was supported by a generous gift from the Cazalot family and the MD Anderson Women’s Cancer Moonshot Program. Fluorescence microscopy analysis was conducted at the Integrated Microscopy Core at Baylor College of Medicine and the Center for Advanced Microscopy and Image Informatics (CAMII) with funding from NIH (DK56338, CA125123, ES030285), and CPRIT (RP150578, RP170719), the Dan L Duncan Comprehensive Cancer Center, and the John S. Dunn Gulf Coast Consortium for Chemical Genomics. Seahorse was conducted at the Mouse Metabolism and Phenotyping Core supported by NIH UM1HG006348 and NIH R01DK114356, NIH R01HL130249. Metabolomics studies were conducted at The MD Anderson Cancer Center Metabolomics Core Facility supported by NIH grants S10OD012304-01 and P30CA016672. STR cell line validation was conducted by the Cytogenetics and Cell Authentication Core at M.D. Anderson Cancer Center. Immunohistochemistry was conducted at the Breast Center Pathology Core and Lab was created to support the research and clinical activities of the Breast Center at Baylor College of Medicine, supported by the Breast Center and a variety of research grants awarded to its faculty, including one of only nine Specialized Programs of Research Excellence (SPORE) in Breast Cancer granted by the National Institute of Health. Vectra microscopy and analysis was conducted with the Pathology and Histology at Baylor College of Medicine with funding from P30 Cancer Center Support Grant (NCI-CA125123).

Funding

GVE is a CPRIT Scholar in Cancer Research. Funding sources that supported this work include the Cancer Prevention and Research Institute of Texas RR200009 (to GVE); NIH 1K22CA241113-01 (to GVE), P30CA016672 (to PLL), P30 CA125123 (to TW), 1R01HD102149-01A1 (to WP), T32GM139534 (to KEP) T32GM136560-02 (to MJB), and F31CA275397 (to KEP); a Myra Branum Wilson Baylor Research Advocates for Student Scientists Scholarship (to MJB); a charitable gift from Sage Patient Advocates (to GVE); a Breast Cancer Alliance Young Investigator Grant (to GVE), and National Science Foundation Graduate Research Fellowship 2140736 (to MJB).

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Authors and Affiliations

  1. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA

    Mokryun L. Baek, Junegoo Lee, Katherine E. Pendleton, Mariah J. Berner, Emily B. Goff, Bora Lim & Gloria V. Echeverria

  2. Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA

    Mokryun L. Baek, Junegoo Lee, Katherine E. Pendleton, Mariah J. Berner, Emily B. Goff, Tao Wang, Bora Lim & Gloria V. Echeverria

  3. Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    Mokryun L. Baek, Junegoo Lee, Katherine E. Pendleton, Mariah J. Berner, Emily B. Goff, Bora Lim & Gloria V. Echeverria

  4. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    Mokryun L. Baek, Junegoo Lee, Katherine E. Pendleton, Mariah J. Berner, Emily B. Goff & Gloria V. Echeverria

  5. Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Lin Tan, Sara A. Martinez, Iqbal Mahmud & Philip L. Lorenzi

  6. Shared Equipment Authority, Rice University, Houston, TX, USA

    Matthew D. Meyer

  7. Department of Pathology, Texas Children’s Hospital, Houston, TX, USA

    James P. Barrish

  8. Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA

    Weston Porter

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Contributions

MLB and GVE were responsible for overall study design, experimentation, data interpretation, and writing of the paper. JL conducted animal experiments and quantitative PCR under the supervision of GVE. KEP conducted IHC, co-IF, Vectra, and assisted with Seahorse assays under the supervision of GVE. MJB conducted mitochondrial assays and western blotting under the supervision of GVE. EBG assisted with confocal microscopy image analysis under the supervision of GVE. LT and SAM conducted metabolomics sample processing under the supervision of PLL. IM conducted metabolomics data analysis under the supervision of PLL. TW conducted statistical analyses. MM conducted TEM of TNBC cell lines. BL assisted with design and analysis of chemotherapy treatments. JPB conducted TEM of PDX tumor tissues and assisted with analysis. WP assisted with analysis of TEM and mitochondria function experiments. PLL oversaw metabolomics experiments and analyses. All authors have critically read, edited, and approved the final version of this paper.

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Correspondence to Gloria V. Echeverria.

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BL received research funding from Genentech, Merck, Puma Biotechnology, and Takeda oncology and consulting fees from Astra Zeneca, Novartis, Natera, Celcuity, and Pfizer. All other authors have nothing to disclose.

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Baek, M.L., Lee, J., Pendleton, K.E. et al. Mitochondrial structure and function adaptation in residual triple negative breast cancer cells surviving chemotherapy treatment. Oncogene 42, 1117–1131 (2023). https://doi.org/10.1038/s41388-023-02596-8

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