Chemoresistance constitute nowadays the major contributor to therapy failure in most cancers. There are main factors that mitigate cell response to therapy, such as target organ, inherent sensitivity to the administered compound, its metabolism, drug efflux and influx or alterations on specific cellular targets, among others. We now know that intrinsic properties of cancer cells, including metabolic features, substantially contribute to chemoresistance. In fact, during the last years, numerous reports indicate that cancer cells resistant to chemotherapy demonstrate significant alterations in mitochondrial metabolism, membrane polarization and mass. Metabolic activity and expression of several mitochondrial proteins are modulated under treatment to cope with stress, making these organelles central players in the development of resistance to therapies. Here, we review the role of mitochondria in chemoresistant cells in terms of metabolic rewiring and function of key mitochondria-related proteins.

Cancer cells exhibit altered metabolism, a phenomenon described a century ago by Otto Warburg. However, metabolic drug targeting is considered an underutilized and poorly understood area of cancer therapy. Metformin, a metabolic drug commonly used to treat type 2 diabetes, has been associated with lower cancer incidence, although studies are inconclusive concerning effectiveness of the drug in treatment or cancer prevention. The aim of this study was to determine how glucose concentration influences cancer cells’ response to metformin, highlighting why metformin studies are inconsistent. We used two colorectal cancer cell lines with different growth rates and clinically achievable metformin concentrations. We found that fast growing SW948 are more glycolytic in terms of metabolism, while the slower growing SW1116 are reliant on mitochondrial respiration. Both cell lines show inhibitory growth after metformin treatment under physiological glucose conditions, but not in high glucose conditions. Furthermore, SW1116 converges with SW948 at a more glycolytic phenotype after metformin treatment. This metabolic shift is supported by changed GLUT1 expression. Thus, cells having different metabolic phenotypes, show a clear differential response to metformin treatment based on glucose concentration. This demonstrates the importance of growth conditions for experiments or clinical studies involving metabolic drugs such as metformin.

Background To our current understanding, solid tumors depend on suppressed local immune reactions, often elicited by the interaction between tumor cells and tumor microenvironment (TME) components. Despite an improved understanding of anti-cancer immune responses in the TME, it is still unclear how immuno-suppressive TME are formed and how some cancer cells survive and metastasize. Methods To identify the major adaptations that cancer cells undergo during tumor development and progression, we compared the transcriptome and proteome from metastatic 66cl4 and non-metastatic 67NR cell lines in culture versus their corresponding mouse mammary primary tumors. Using confocal microscopy, RT-qPCR, flow cytometry and western blotting, we studied the signaling pathway and the mechanisms involved. In addition, we used public gene expression data from human breast cancer biopsies to evaluate the correlation between gene expression and clinical outcomes in patients. Results We found that type I interferon (IFN-I) response was a key differentially regulated pathway between metastatic and non-metastatic cell lines and tumors. The IFN-I response was active in metastatic cancer cells in culture and markedly dampened when these cells formed primary tumors. Interestingly, the opposite was observed in non-metastatic cancer cells and tumors. Consistent with an active IFN-I response in culture, the metastatic cancer cells displayed elevated levels of cytosolic DNA from both mitochondria and ruptured micronuclei with concomitant activation of cGAS-STING signaling. Interestingly, decreased IFN-I-related gene expression in breast cancer biopsies correlated with an unfavourable prognosis in patients. Conclusion Our findings show that IFN-I response is dampened in the tumors with the metastatic ability and lower IFN-I expression predicts poor prognosis in triple-negative and HER2 enriched breast cancer patients. This study highlights the possibility of reactivating the IFN-I response as a potential therapeutic strategy in breast cancer. Graphical abstract

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