27 research outputs found
Mitochondrial and ribosomal biogenesis are new hallmarks of stemness, oncometabolism and biomass accumulation in cancer : mito-stemness and ribo-stemness features
Using proteomics analysis, we previously compared MCF7 breast cancer cells grown as 3D tumor spheres, with the same cell line grown as monolayers. Our results indicated that during 3D anchorageâindependent growth, the cellular machinery associated with i) mitochondrial biogenesis and ii) ribosomal biogenesis, were both significantly increased. Here, for simplicity, we refer to these two new oncogenic hallmarks as âmitoâstemnessâ and âriboâstemnessâ features. We have now applied this same type of strategy to begin to understand how fibroblasts and MCF7 breast cancer cells change their molecular phenotype, when they are coâcultured together. We have previously shown that MCF7âfibroblast coâcultures are a valuable model of resistance to apoptosis induced by hormonal therapies, such as Tamoxifen and Fulvestrant. Here, we directly show that these mixed coâcultures demonstrate the induction of mitoâstemness and riboâstemness features, likely reflecting a mechanism for cancer cells to increase their capacity for accumulating biomass. In accordance with the onset of a stemâlike phenotype, KRT19 (keratin 19) was induced by ~6âfold during coâculture. KRT19 is a wellâestablished epithelial CSC marker that is used clinically to identify metastatic breast cancer cells in sentinel lymph node biopsies. The potential molecular therapeutic targets that we identified by labelâfree proteomics of MCF7âfibroblast coâcultures were then independently validated using a bioinformatics approach. More specifically, we employed publicallyâavailable transcriptional profiling data derived from primary tumor samples from breast cancer patients, which were previously subjected to laserâcapture microâdissection, to physically separate breast cancer cells from adjacent tumor stroma. This allowed us to directly validate that the proteins upâregulated in this coâculture model were also transcriptionally elevated in patientâderived breast cancer cells in vivo. This powerful approach for target identification and translational validation, including the use of patient outcome data, can now be applied to other tumor types as well, to validate new therapeutic targets that are more clinically relevant, for patient benefit. Moreover, we discuss the therapeutic implications of these findings for new drug development, drug repurposing and Tamoxifenâresistance, to effectively target mitoâstemness and riboâstemness features in breast cancer patients. We also discuss the broad implications of this âorganelle biogenesisâ approach to cancer therapy
Mitochondrial fission as a driver of stemness in tumor cells : mDIVI1 inhibits mitochondrial function, cell migration and cancer stem cell (CSC) signalling
Mitochondria are dynamic organelles frequently undergoing fission and fusion events to maintain their integrity, bioenergetics and spatial distribution, which is fundamental to the processes of cell survival. Disruption in mitochondrial dynamics plays a role in cancer. Therefore, proteins involved in regulating mitochondrial dynamics are potential targets for treatment. mDIVI1 is an inhibitor of the mitochondrial fission protein DRP1, which induces i) mitochondrial oxidative stress and ii) effectively reduces mitochondrial metabolism. We show here that mDIVI1 is able to inhibit 3D tumorsphere forming capacity, cell migration and stemness-related signalling in breast cancer cells, indicating that mDIVI1 can potentially be used for the therapeutic elimination of cancer stem cells (CSCs)
Proteomic identification of prognostic tumour biomarkers, using chemotherapy-induced cancer-associated fibroblasts
Cancer cells grow in highly complex stromal microenvironments, which through metabolic remodelling, catabolism, autophagy and inflammation nurture them and are able to facilitate metastasis and resistance to therapy. However, these changes in the metabolic profile of stromal cancer-associated fibroblasts and their impact on cancer initiation, progression and metastasis are not well-known. This is the first study to provide a comprehensive proteomic portrait of the azathioprine and taxol-induced catabolic state on human stromal fibroblasts, which comprises changes in the expression of metabolic enzymes, myofibroblastic differentiation markers, antioxidants, proteins involved in autophagy, senescence, vesicle trafficking and protein degradation, and inducers of inflammation. Interestingly, many of these features are major contributors to the aging process. A catabolic stroma signature, generated with proteins found differentially up-regulated in taxol-treated fibroblasts, strikingly correlates with recurrence, metastasis and poor patient survival in several solid malignancies. We therefore suggest the inhibition of the catabolic state in healthy cells as a novel approach to improve current chemotherapy efficacies and possibly avoid future carcinogenic processes
Doxycycline and therapeutic targeting of the DNA damage response in cancer cells : old drug, new purpose
There is a small proportion of cells within a tumour with self-renewing properties, which is resistant to conventional therapy, and is responsible for tumour initiation, maintenance and metastasis. These cells are known as cancer stem cells (CSCs) or tumour-initiating cells (TICs) [1]. Recent publications identify several antibiotics, such as salinomycin or doxycycline, as selective CSCs inhibitors [2-4]. However, the mechanisms of action of these antibiotics on CSCs are not fully understood
Bergamot natural products eradicate cancer stem cells (CSCs) by targeting mevalonate, Rho-GDI-signalling and mitochondrial metabolism
Here, we show that a 2:1 mixture of Brutieridin and Melitidin, termed âBMFâ, has a statin-like properties, which
blocks the action of the rate-limiting enzyme for mevalonate biosynthesis, namely HMGR (3-hydroxy-3-methylglutaryl-
CoA-reductase). Moreover, our results indicate that BMF functionally inhibits several key characteristics
of CSCs. More specifically, BMF effectively i) reduced ALDH activity, ii) blocked mammosphere
formation and iii) inhibited the activation of CSC-associated signalling pathways (STAT1/3, Notch and Wnt/
beta-catenin) targeting Rho-GDI-signalling. In addition, BMF metabolically inhibited mitochondrial respiration
(OXPHOS) and fatty acid oxidation (FAO). Importantly, BMF did not show the same toxic side-effects in normal
fibroblasts that were observed with statins. Lastly, we show that high expression of the mRNA species encoding
HMGR is associated with poor clinical outcome in breast cancer patients, providing a potential companion
diagnostic for BMF-directed personalized therapy
Cancer stem cells (CSCs) : metabolic strategies for their identification and eradication
Phenotypic and functional heterogeneity is one of the most relevant features of cancer cells within different tumor types and is responsible for treatment failure. Cancer stem cells (CSCs) are a population of cells with stem cell-like properties that are considered to be the root cause of tumor heterogeneity, because of their ability to generate the full rep- ertoire of cancer cell types. Moreover, CSCs have been invoked as the main drivers of metastatic dissemination and therapeutic resistance. As such, targeting CSCs may be a useful strategy to improve the effectiveness of classical anticancer therapies. Recently, metabolism has been considered as a relevant player in CSC biology, and indeed, onco- genic alterations trigger the metabolite-driven dissemination of CSCs. More interestingly,
the action of metabolic pathways in CSC maintenance might not be merely a conse- quence of genomic alterations. Indeed, certain metabotypic phenotypes may play a causative role in maintaining the stem traits, acting as an orchestrator of stemness. Here, we review the current studies on the metabolic features of CSCs, focusing on the bio- chemical energy pathways involved in CSC maintenance and propagation. We provide a detailed overview of the plastic metabolic behavior of CSCs in response to microenvironment changes, genetic aberrations, and pharmacological stressors. In addition, we describe the potential of comprehensive metabolic approaches to identify and selectively eradicate CSCs, together with the possibility to âforceâ CSCs within certain metabolic
dependences, in order to effectively target such metabolic biochemical inflexibilities. Finally, we focus on targeting mitochondria to halt CSC dissemination and effectively eradicate cancer
Cancer stem cell metabolism
Cancer is now viewed as a stem cell disease. There is still no consensus on the metabolic characteristics of cancer stem cells, with several studies indicating that they are mainly glycolytic and others pointing instead to mitochondrial metabolism as their principal source of energy. Cancer stem cells also seem to adapt their metabolism to microenvironmental changes by conveniently shifting energy production from one pathway to another, or by acquiring intermediate metabolic phenotypes. Determining the role of cancer stem cell metabolism in carcinogenesis has become a major focus in cancer research, and substantial efforts are conducted towards discovering clinical targets