Understanding the cancer cell phenotype beyond the limitations of current omics analyses

Abstract

Efforts to understand the mechanistic principles driving cancer metabolism and proliferation have been lately governed by genomic, transcriptomic and proteomic studies. This paper analyzes the caveats of these approaches. As molecular biology's central dogma proposes a unidirectional flux of information from genes to mRNA to proteins, it has frequently been assumed that monitoring the changes in the gene sequences and in mRNA and protein contents is sufficient to explain complex cellular processes. Such a stance commonly disregards that post‐translational modifications can alter the protein function/activity and also that regulatory mechanisms enter into action, to coordinate the protein activities of pathways/cellular processes, in order to keep the cellular homeostasis. Hence, the actual protein activities (as enzymes/transporters/receptors) and their regulatory mechanisms ultimately dictate the final outcomes of a pathway/cellular process. In this regard, it is here documented that the mRNA levels of many metabolic enzymes and transcriptional factors have no correlation with the respective protein contents and activities. The validity of current clinical mRNA‐based tests and proposed metabolite biomarkers for cancer detection/prognosis is also discussed. Therefore, it is proposed that, to achieve a thorough understanding of the modifications undergone by proliferating cancer cells, it is mandatory to experimentally analyze the cellular processes at the functional level. This could be achieved (a) locally, by examining the actual protein activities in the cell and their kinetic properties (or at least kinetically characterize the most controlling steps of the pathway/cellular process); (b) systemically, by analyzing the main fluxes of the pathway/cellular process, and how they are modulated by metabolites, all which should contribute to comprehending the regulatory mechanisms that have been altered in cancer cells. By adopting a more holistic approach it may become possible to improve the design of therapeutic strategies that would target cancer cells more specifically.

Mitochondrial Respiration in Human Colorectal and Breast Cancer Clinical Material Is Regulated Differently

“…The functional units within cells are often macromolecular complexes rather than single species [20]. In case of OXPHOS, it has been shown that complexes of the respiratory chain can form assemblies—supercomplexes—that lead to kinetic and possibly homeostatic advantages [21].…”

Mitochondrial-Targeted Decyl-Triphenylphosphonium Enhances 2-Deoxy-D-Glucose Mediated Oxidative Stress and Clonogenic Killing of Multiple Myeloma Cells

“…Microarray results with human MM biopsies suggest that increased expression of glycolytic genes may predict poorer overall survival outcomes. However, a tight correlation between gene transcription and pathway functionality may always not hold true [97]. Further studies in primary MM samples are required to show a direct correlation between glycolysis and overall survival outcomes.…”

Recreating complex pathophysiologies in vitro with extracellular matrix surrogates for anticancer therapeutics screening

“…Bioinformatics [105,106], DNA sequencing [107,108], omics [109,110] and algorithm (e.g., COXEN) [111,112] tools have allowed the identification of chemokines and cytokines involved in immune contexture (analysis of the location, density and functional orientation of the different immune cell populations [113]) and proteomic, genomic, transcriptomic and epigenomic alterations in cancers, consequently enabling a more rational design in target therapy discovery, cancer prevention and therapy. Outputs of such investigations have enabled the development of CIVO™ technology, for example, that enables the simultaneous assessment of up to eight drugs or drug combinations within a solid tumour in vivo [114].…”