Although it is well known that physical activity can prevent cancer, the molecular mechanisms behind these effects are poorly understood. During exercise, extracellular vesicles (EVs) are released into the circulation and mediate tissue crosstalk with potential effects on tumour cells and immune tumour microenvironment. The overall aim of CancerBeat is to characterize the molecular cargo of exercise-induced EVs and explore their effects on breast cancer (BC) progression in vitro and in vivo.
Cancer is a complex multifactorial disease, but one feature common to all cancer cells is that they require a lot of energy for rapid growth. The knowledge about the cancer mechanisms is still lacking and information is contradictory, despite, that cancer cell energy metabolism has been studied for nearly a hundred years. The working hypothesis of our project is that the altered energy metabolism of cancer cells contains clues to cancer therapy: by blocking the energy transport of tumor cells, we directly influence their growth. Considering that the cellular chemical energy production occurs in mitochondria,we will thoroughly characterize the metabolic kinases and VDAC permeability of colorectal and breast cancer by using fluxomics, proteomics, and mathematical modeling. We use appropriate in vitro tissue cultures in parallel to postoperative tissue samples. From this data, we will construct the mathematical models for the prognosis and treatment evaluation of both types of cancer.
Increasing evidence indicates reciprocal dysregulation between energy-producing pathways (e.g. glycolysis) and oxidative stress in initiation and progression of neurodegeneration. Altered activity of bioenergetics pathways and increased levels of oxidative stress in the brain are common early features of many forms of neurodegeneration. On the other hand, antioxidant response and activity of major biochemical pathways do not reciprocate real-life situations in the standard in-vitro cell culture conditions, which hamper the validity of mechanistic studies and also evaluation of the efficacy of drug candidates with neuroprotective potential. The aim of this project is to optimize the cell culture parameters to better mimic the in vivo conditions with respect to the interplay of antioxidant response and activity of bioenergetics pathways. Results of this study will be used to design a platform suitable for the high throughput screening of novel neuroprotective drug candidates.
The aim of this project is to define the mechanisms that cause critical shifts in the regulation of energy metabolism and the alterations in the cytoskeleton structure in tumor cells in comparison with normal cells. Recently developed direction, Molecular System Bioenergetics (MSB), which is an important part of Systems Biology, provides groundbreaking solutions in the field of cancer and muscle cells bioenergetics. Approach of MSB and its research methods, such as metabolic control analysis, proteomics and metabolomics techniques are planned to be used in order to identify and quantify the cellular regulation and to map tumor-specific bioenergetic profiles. The crucial benefit in this case and the great significance for further diagnostic purposes lies in the use of in vivo studies. The project is a continuation of our prior fundamental studies within the framework of MSB (SF0180114Bs08) directed on the clarification of the regulation of bioenergetic processes in muscle cells in situ.
Currently, it is not clear how the transformation from normal to cancer metabolism proceeds, how normal mechanisms of coordination between glycolytic and oxidative networks degrade into the most primitive model of glycolytic energy metabolism. Our resent studies clearly showed the important role of the ATP Synthasome-mitochondrial creatine kinase-voltage-dependent anion channel (VDAC)-tubulin b2 system (mitochondrial interactosome, MI) in regulation of respiration and energy fluxes in cardiac cells. Recently it was discovered the existence of a supercomplex ATP Synthasome-VDAC-hexokinase-2 in cancer cells that helped partly to understanding the Warburg effect. The absence of b2-tubulin isotype in isolated mitochondria and in HL-1 cells (cancerous cells of cardiac phenotype) resulted in increased apparent affinity of oxidative phosphorylation for exogenous ADP. Our working hypothesis is that alterations in the structure of MI may contribute in carcinogenesis. In cancer cells the interaction of tubulin-VDAC is replaced by the interaction of HK-VDAC resulting in a modification of the metabolic regulation with exhibition of the aerobic glycolytic profile and several anabolic reactions. These studies have provided new evidence for a variable bioenergetics signature of human tumors. Innovative strategies of bioenergetic cancer medicine will emanate from this basic knowledge and the first step consists in the understanding of the modalities of cancer cell energy production. Our second main goal is describe quantitatively the distribution of control between the complexes of energy transfer in MI in cancer cells using clinical material and cell cultures. In this context an interesting and important task will be to apply the methods of Metabolic Control Analysis. Novelty of the project is to evaluate the mechanisms that are involved in the regulation of oxidative phosphorylation in breast cancer clinical material and different lines of tumor cells. Enhancement of tubulin-VDAC interaction maintains and induces oxidative regulation of mitochondrial respiration with micro-compartmentation of adenine nucleotides could become one of new therapeutic targets in cancer management. We plan to perform complex experimental studies directed on mechanisms of energy metabolism of tumor cells with purpose to find possible links between bioenegrtic parameters and prognosis of cancer, also developing cancer therapeutics and probably its impact in identifying novel cancer biomarkers.
