Abstract 1435: The distribution of Tumor Treating Fields is affected by cell confluence and pores in the membrane
Authors: Marciano Tal , Levi Shay , Fedorov Eduard , Bomzon Zeev 
Published: July 2021

Abstract
Introduction: Better understanding of the interaction between Tumor Treating Fields (TTFields) and living cells would help to elaborate on its mechanism of action. Numerical simulations investigating the electric field distribution within isolated cells have shown that during metaphase a uniform electric field forms within the rounded cells, and during cytokinesis a non-uniform field forms at the furrow, leading to strong dielectrophoretic (DEP) forces that can disrupt cell division. However, preclinical studies have shown that TTFields influence cells during earlier stages of cell division. Hence, field non-uniformity within the cell during cytokinesis cannot provide a full explanation for how TTFields exerts an anti-mitotic effect on cells. We hypothesized that strong DEP forces could arise at the boundaries between cells and in pores on the membrane when applying TTFields to cell culture. We tested this hypothesis by using numerical simulations to investigate how the clustering of cells and pores within the membrane influence TTFields distribution.
Methods: COMSOL was used to numerically simulate delivery of TTFields to clusters of round cells placed in a hexagonal arrangement. The influence of the distance between the cells on field distribution was investigated. The effect of pores in the cell membrane on field distribution was also investigated. A generic analytical model was developed for predicting conditions for field amplification in the TTFields frequencies.
Results: Placing round cells in clusters separated by ~10 nm resulted in regions of highly non-uniform fields within the cells and very strong DEP forces at the intercellular level. Maximum field intensities between cells were observed at 200 kHz. Very strong gradients in the electric field were observed around pores placed in the membrane, and a strong field amplification was observed at 200 kHz regardless of the pore size. For a 10 nm pore, up to 450 V/cm is generated at the pore's vicinity. 100 nm pores generate more than 130 V/cm for an applied external field of 1 V/cm. Electroporation generates enough energy for overcoming the internal KT energy at pores that are ≤30 nm and may allow for dipole alignment.
Conclusions: Cells in close proximity to one another creates gradients in the electric field, and are associated with strong DEP forces that enhance the effects of TTFields on cells. Strong DEP forces in the membrane may provide a physical mechanism by which TTFields enhance membrane permeability. The strong field amplification could cause local heating, particle diffusion, and impact the cytoskeleton in the vicinity of membrane pores. These simulations have validated a generic model that predicts the conditions for strong field amplifications in cells at TTFields frequencies, allowing further elaboration of the mechanism of action. Our model fits well with other analytical models; the furrow model, cells in confluence, or electroporation.
Citation Format: Tal Marciano, Shay Levi, Eduard Fedorov, Zeev Bomzon. The distribution of Tumor Treating Fields is affected by cell confluence and pores in the membrane [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1435.