Cancer stem cells (CSCs) are the leading cause of cancer initiation, metastasis and chemoresistance, thus eliminating them could lead to permanent cancer eradication. CSCs have a unique genotipic phenotype and exhibit metabolic plasticity based on the tumor
microenvironment.
we compared the metabolic fingerprints of H460 cancer cell culture cells grown as adherent (2D) or as three-dimensional (3D) tumor spheroids in a spheroid medium and low- serum medium. Tumor spheroids are an optimal in vitro model to enrich the CSCs subpopulations and to mimic the trascrittomic shift and the 3D inter-cellular transport of nutrients and oxygen.
Multivariate analysis showed a significant shift from the 2D typical oxidative metabolism to a glycolytic and gluconeogenesis metabolism in 3D conditions. Indeed, 3D cultures showed changes of glycolytic intermediates (D-Glucose-6P, D-Fructose-6P, Dihydroxiacetone phosphate) as well as intracellular accumulation of lactic acid.
In 3D the intracellular concentration of AAs was strongly reduced compared to 2D, thus suggesting either higher utilization or reduced production; the latter, could be associated with the lower proliferation rate of H460 cells in 3D cultures. Strikingly, 2D cultures showed use aspartate to generate asparagine that support mTOR, this is not observed in 3D. Overall, this study indicates that lung CSCs use glycolysis/gluconeogenesis and AAs metabolism to satisfy their energy demands and these could certainly play a key role in the acquisition of stemness-like properties. Further experiments, i.e. transcriptional analysis will be performed to validate our preliminary results. Metabolomics approaches are powerful tools for the direct profiling of cell metabolism and to uncover mechanisms of transcriptional activation of metabolic pathway in CSCs.
Despite the advances in the early diagnosis and the generation of new targeted therapies, lung cancer is still the leading cause of cancer related mortality worldwide. At diagnosis most patients present with locally advanced or metastatic disease of which malignant pleural effusions (MPEs) represent a frequent complication. Treatment failures can be attributed to the presence of a subpopulation of cancer cells, defined cancer stem cells (CSCs), with the properties of self-renewal, capability to generate differentiated cancer cells and resistance to therapies.
A hallmark of tumour progression and recurrence is the ability sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis.
Conceptual progress in the last decade has added emerging hallmark of potential generality to this list: reprogramming of energy metabolism. Cancer Stem cells involves major reprogramming of cellular energy metabolism in order to support continuous cell growth and proliferation, replacing the metabolic program that operates in most normal tissues and fuels the physiological operations of the associated cells. Otto Warburg first observed an anomalous characteristic of cancer cell energy metabolism even in the presence of oxygen, cancer cells can reprogram their glucose metabolism, and thus their energy production, by limiting their energy metabolism largely to glycolysis, leading to a state that has been termed "aerobic glycolysis". The existence of this metabolic switch in cancer cells has been substantiated in the ensuing decades.
Furthermore, glycolytic fueling has been shown to be associated with activated oncogenes (RAS, MYC) and mutant tumor suppressors (TP53), can be further accentuated under the hypoxic conditions that operate within many tumors. Recognition of the widespread investigation of metabolic and trascriptomic change of these concepts will increasingly affect the development of new means to treat lung cancer. Lipid metabolism will be studied to identify new molecular mechanisms involved in the progression of lung cancer, in order to identify innovative strategies based on the identifications of CSCs targets. This may be a promising strategy for overcoming the resistance to conventional chemiotherapy.
In addition, via the bioinformatics analysis on the integrated multi-omics data, along with construction of molecular interaction network, we will be identified molecular targets, and underlying signaling pathways associated with CSCs in lung cancer. In conclusion we will to reveal the interplay between lipid metabolism and trascriptomic analysis in the determination of metabolic reprogramming to develop new strategies based on targeting of CSCs.