Mathematical Modeling of Non-Small-Cell Lung Cancer Biology through the Experimental Data on Cell Composition and Growth of Patient-Derived Organoids.

Mathematical models of non-small-cell lung cancer are powerful tools that use clinical and experimental data to describe various aspects of tumorigenesis. The developed algorithms capture phenotypic changes in the tumor and predict changes in tumor behavior, drug resistance, and clinical outcomes of anti-cancer therapy. The aim of this study was to propose a mathematical model that predicts the changes in the cellular composition of patient-derived tumor organoids over time with a perspective of translation of these results to the parental tumor, and therefore to possible clinical course and outcomes for the patient. Using the data on specific biomarkers of cancer cells (PD-L1), tumor-associated macrophages (CD206), natural killer cells (CD8), and fibroblasts (αSMA) as input, we proposed a model that accurately predicts the cellular composition of patient-derived tumor organoids at a desired time point. Combining the obtained results with "omics" approaches will improve our understanding of the nature of non-small-cell lung cancer. Moreover, their implementation into clinical practice will facilitate a decision-making process on treatment strategy and develop a new personalized approach in anti-cancer therapy.

Comparison of EMT-Related and Multi-Drug Resistant Gene Expression, Extracellular Matrix Production, and Drug Sensitivity in NSCLC Spheroids Generated by Scaffold-Free and Scaffold-Based Methods.

Multicellular 3D tumor models are becoming a powerful tool for testing of novel drug products and personalized anticancer therapy. Tumor spheroids, a commonly used 3D multicellular tumor model, more closely reproduce the tumor microenvironment than conventional 2D cell cultures. It should be noted that spheroids can be produced using different techniques, which can be subdivided into scaffold-free (SF) and scaffold-based (SB) methods. However, it remains unclear, to what extent spheroid properties depend on the method of their generation. In this study, we aimed to carry out a head-to-head comparison of drug sensitivity and molecular expression profile in SF and SB spheroids along with a monolayer (2D) cell culture. Here, we produced non-small cell lung cancer (NSCLC) spheroids based on human lung adenocarcinoma cell line A549. Drug sensitivity analysis of the tested cell cultures to five different chemotherapeutics resulted in IC50 (A549-SB) > IC50 (A549-SF) > IC50 (A549-2D) trend. It was found that SF and SB A549 spheroids displayed elevated expression levels of epithelial-to-mesenchymal transition (EMT) markers and proteins associated with drug resistance compared with the monolayer A549 cell culture. Enhanced drug resistance of A549-SB spheroids can be a result of larger diameters and elevated deposition of extracellular matrix (ECM) that impairs drug penetration into spheroids. Thus, the choice of the spheroid production method can influence the properties of the generated 3D cell culture and their drug resistance. This fact should be considered for correct interpretation of drug testing results.