Movement of Mitochondria with Mutant DNA through Extracellular Vesicles Helps Cancer Cells Acquire Chemoresistance

Abstract

Triple negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer with the worst prognosis after chemo‐ or radiation therapy. This is mainly due to the development of cancer chemoresistance accompanied by tumor recurrence. In this work, we investigated a new mechanism of acquired chemoresistance of TNBC cells. We showed that extracellular vehicles (EVs) of chemoresistant TNBC cells can transfer mitochondria to sensitive cancer cells, thus increasing their chemoresistance. Such transfer, but with less efficiency, can be carried out over short distances using tunneling nanotubes. In addition, we showed that exosome fractions carrying mitochondria from resistant TNBC cells contribute to acquired chemoresistance by increasing mtDNA levels with mutations in the mtND4 gene responsible for tumorigenesis. Blocking mitochondrial transport by exosome inhibitors, including GW4869, reduced acquired TNBC chemoresistance. These results could lead to the identification of new molecular targets necessary for more effective treatment of this type of cancer.

Therapeutic Implications of the Drug Resistance Conferred by Extracellular Vesicles Derived from Triple-Negative Breast Cancer Cells

“…A recent study demonstrated that TNBC-EVs derived from chemo-resistant cells increase chemoresistance in chemo-sensitive cancer cells by transferring mitochondria with mutations in the MT-ND4 gene [ 95 ]. MT-ND4 encodes an NADH-ubiquinone oxidoreductase chain 4 protein, one of seven components of the respiratory complex I.…”

MitoEVs: A new player in multiple disease pathology and treatment

“…Circulating mtDNA‐rich EVs were found in insulin therapy‐antagonized metastatic breast cancer patients, which might act as a pro‐oncogenic signal to induce endocrine therapy resistance in oxidative phosphorylation‐dependent breast cancer cells (Sansone et al., 2017 ). EVs released by chemoresistant triple‐negative breast cancer cells could deliver functional mitochondria to sensitive triple‐negative breast cancer cells, leading to increased chemoresistance and tumorigenesis (Abad & Lyakhovich, 2022 ). Likewise, EVs from tumour‐activated stromal cells delivered mitochondria to malignant glioma cells, resulting in resistance to cancer radiotherapy and chemotherapy (Salaud et al., 2020 ).…”

Non-Classical Intercellular Communications: Basic Mechanisms and Roles in Biology and Medicine

“…In a similar study, Thomas et al [ 228 ] reported that MSCs are able to package functional mitochondria into extracellular vesicles that can be transferred to chondrocytes without direct intercellular interactions. A new mechanism of acquired chemoresistance of triple-negative breast cancer cells by the EV-mediated transfer of mitochondria was shown by Abad et al [ 229 ]. On the other hand, an interesting study by Crewe et al [ 230 ] demonstrated that the injection of EVs released by stressed adipocytes and containing oxidatively damaged mitochondrial particles may have, contrary to expectations, a positive effect and alleviate cardiac ischemia in mice, representing a first example of interorgan mitohermesis in vertebrates.…”