The drug induction of cell senescence shows high potential for cancer treatment. The research project focuses on the investigation of bioelectrical parameters and their possible role in the formation of senescence in resistant lung cancer cells treated with appropriate CDK4/6 inhibitors. By looking at biochemical and electrophysiological aspects, the study aims to gain a deeper understanding of senescence mechanisms, which may form the basis for innovative, combined therapeutic approaches for the treatment of lung cancer.
Computational modeling and simulation of cell electrophysiology is an established tool for the analysis of bioelectricity of excitable cells. However, only a few mathematical models have been developed to simulate bioelectric cell functions of nonexcitable cells, e.g., to describe voltage-dependent modulation of cell secretion, calcium dynamics, or activation of T lymphocytes. These first experiments, based on the consideration of the most important ion channel types in a mathematical model, impressively demonstrate the potential of such models for an accurate simulation and reliable prediction of cellular processes and activities even in non-excitable cells.
In carcinogenesis, the membrane potential Vm generated by ion channel and pump proteins is important for determining the state of differentiation and proliferation. One possibility for carcinogenesis is the disruption of electrical gradients or mechanisms by which they are sensed by cells. Vm is thus an important non-genetic biophysical biomarker candidate of the cancer microenvironment that regulates growth and carcinogenesis. Cancerous and proliferative tissues are generally more positively charged or depolarized than nonproliferative cells. Pharmacological blockade of ion channels is therefore a popular method to "perturb" the membrane potential Vm. Membrane potential has been studied as an important regulator of proliferation in a number of cell types, suggesting that modulation of Vm is required for both G1/S phase and G2/M phase transitions.
The in silico lung cancer cell model project now aims to further develop the world's first digital ion current model of a human A549 lung adenocarcinoma cell, published in 2021, by using a hidden Markov modeling (HMM) approach and data from patch clamp measurements for model parameterization and validation. First, based on our preliminary work, the original cell model will be extended to include additional plasmalemmal ion channels and a description of intracellular calcium dynamics. In the next step, the basic model of cell cycle phase G0 will be adapted and reparameterized with respect to the number of expressed ion channels, function and interaction with other channels during the transition from one cell cycle phase to another phase (G0, G1, S, G2/M). For model validation, selected scenarios of ion channel modulations are performed by comparing model simulations with experimental data. The model is then used to investigate two highly relevant research questions in human lung adenocarcinoma using model simulations and laboratory experiments.
We here present for the first time an experimentally validated in silico cell model of a lung cancer cell line that allows a deeper understanding of the potential roles and interactions of ion channels in tumor development and progression through targeted modulation of selected ion channels using in silico simulations and in vitro measurements. Specifically, inhibition of CRAC channels is expected to significantly alter local calcium concentration and impair or disrupt KCa3.1 channel activity, thereby impeding the G1/S transition and arresting the cell by depolarizing the membrane potential.
Background: Traumatic brain injury (TBI) is a leading cause of death and disability among young adults. The impairment of the often very young patients in daily life is a heavy burden for the affected person and leads to high healthcare costs. In recent years, electrostimulation of neurons has been suggested a promising approach to induce functional recovery of injured neuronal connections. However, standard electrode stimulation techniques require invasive methods and wiring of the patient.
Purpose: We aim to combat TBI-induced disabilities by re-establishing neuronal connectivity. We will use light-sensitive semiconductors (photocaps) made from industrial colorants. They are easily available, stable, and non-toxic. Photocaps enable electrical stimulation of neurons with safe light intensities without the need for external wiring.
Hypothesis: We suppose that the stimulation of neuronal cells via light-activated photocaps fosters functional recovery after TBI.
Approach: In a multidisciplinary research approach we investigate the photocaps’ performance and effects on living systems. Cultured cells are an invaluable tool to develop optimal stimulation parameters before progressing to healthy and injured brain tissue. We will investigate the optimal time window after TBI in which stimulation yields the most extensive regenerative results. Our interdisciplinary research program brings together young independent researchers with backgrounds from neuroscience (Dr. Muammer Ücal), structural biology (Dr. Karin Kornmüller), electrophysiology (Dr. Susanne Scherübel) and electrical engineering (Dr. Theresa Rienmüller). Experiments will be conducted at the Medical University of Graz and Graz University of Technology.