Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBPα-induced fatty acid β-oxidation of IDH1 mutant cells. While IDH1 mutant inhibitor reduced 2-HG oncometabolite and CEBPα methylation, it failed to reverse FAO and OxPHOS. These mitochondrial activities were maintained through the inhibition of Akt and enhanced activation of peroxisome proliferator-activated receptor-γ coactivator-1 PGC1α upon IDH1 mutant inhibitor. Accordingly, OxPHOS inhibitors improved anti-AML efficacy of IDH mutant inhibitors in vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors.

Breast cancer (BC) is the first worldwide most frequent cancer in both sexes and the most commonly diagnosed in females. Although BC mortality has been thoroughly declining over the past decades, there are still considerable differences between women diagnosed with early BC and when metastatic BC is diagnosed. BC treatment choice is widely dependent on precise histological and molecular characterization. However, recurrence or distant metastasis still occurs even with the most recent efficient therapies. Thus, a better understanding of the different factors underlying tumor escape is mainly mandatory. Among the leading candidates is the continuous interplay between tumor cells and their microenvironment, where extracellular vesicles play a significant role. Among extracellular vesicles, smaller ones, also called exosomes, can carry biomolecules, such as lipids, proteins, and nucleic acids, and generate signal transmission through an intercellular transfer of their content. This mechanism allows tumor cells to recruit and modify the adjacent and systemic microenvironment to support further invasion and dissemination. By reciprocity, stromal cells can also use exosomes to profoundly modify tumor cell behavior. This review intends to cover the most recent literature on the role of extracellular vesicle production in normal and cancerous breast tissues. Specific attention is paid to the use of extracellular vesicles for early BC diagnosis, follow-up, and prognosis because exosomes are actually under the spotlight of researchers as a high-potential source of liquid biopsies. Extracellular vesicles in BC treatment as new targets for therapy or efficient nanovectors to drive drug delivery are also summarized.

Extracellular vesicles: General features and usefulness in diagnosis and therapeutic management of colorectal cancer

The sensitive and specific detection of circulating tumor cells holds great promise for more accurate staging of cancer patients. Several reverse transcription-PCR (RT-PCR) procedures based on tissue-specific mRNA expression are now able to detect one cell derived from a given tissue among >10 peripheral nucleated blood cells [PNBCs; for a review, see (1)]. However, even for a single marker, highly discrepant results have been observed among the available clinical studies; e.g., the frequencies of positive prostate-specific antigen (PSA) RT-PCR results range from 25% (2) to 80% (3) in patients with metastatic prostate cancer (CaP), blurring the clinical relevance of these assays. Standardization and quality control in molecular diagnosis are crucial to the solution of this issue. We have previously studied factors potentially affecting RT-PCR results (4), and this current work focuses on the approaches for harvesting prostate cells among nucleated blood cells.

Mitochondrial dysfunctions that were not discovered during preclinical and clinical testing have been responsible for at least restriction of use as far as withdrawal of many drugs. To solve mitochondrial machinery complexity, integrative methodologies combining different data, coupled or not to mathematic modelling into systems biology, could represent a strategic way but are still very hard to implement. These technologies should be accurate and precise to avoid accumulation of errors that can lead to misinterpretations, and then alter prediction efficiency. To address such issue, we have developed a versatile functional energy metabolism platform that can measure quantitatively, in parallel, with a very high precision and accuracy, a high number of biological parameters like substrates or enzyme cascade activities in essential metabolism units (glycolysis, respiratory chain ATP production, oxidative stress...) Its versatility (our platform works on either cell lines or small animals and human samples) allows cell metabolism pathways fine tuning comparison from preclinical to clinical studies. Applied here to OXPHOS and/or oxidative stress as an example, it allows discriminating compounds with acute toxic effects but, most importantly, those inducing low noise chronic ones.