Multi-scale based software for effective analysis of anticancer drug efficacy in a computer simulated target environment

• Main Author: Muniraj, Vivek Sheraton
• Other Authors: Peter M.A. Sloot
• Format: Theses and Dissertations
• Language: English
• Published: 2019
• Subjects: Engineering::Computer science and engineering::Computing methodologies::Simulation and modeling
• Online Access: https://hdl.handle.net/10356/105587; http://hdl.handle.net/10220/50150
• Institution: Nanyang Technological University

Efficacy of chemotherapeutic cancer treatment varies from patient to patient. This variability can be attributed to the differences in the biological characteristics of the cancer cells. The effects of the biological characteristics on chemotherapy outcomes are widely studied. In most cases, such as in drug testing, it is assumed that a drug working on a biological cell type will continue to work with the same efficacy on patients having the same cell type. However, even in patients having phenotypically and genotypically identical cancer cells, the treatment efficacies vary between each other. These deviations arise from the cell-level biophysical characteristic variations in the cells that make up the tumor microenvironment. In addition to affecting the treatment outcomes, the microenvironment also alters the evasive capability of cancer cells. The tumor microenvironment therefore acts as a modifier of chemotherapeutic effects and enabler of chemotherapy evasion of the cancer cells. To completely understand the effects of microenvironment on chemotherapy outcomes, it is necessary to analyse the cell-level and tissue level biophysical evasion mechanisms of the cancer cells. These mechanisms aid in drug effect evasion and/or promote metastases. In this thesis, a simulation framework is developed for numerical modelling and simulation of interactions between cancerous tumor cells and their microenvironment. Three computational and experimental studies are included. They include, study of the, effects of chemotherapy on homogenous tumor population, influence of tumor microenvironment on the development of invadopodia structures and the transformation of benign tumor to a malignant tumor. The mechanisms of action and efficacy of chemotherapy drugs, at cell population levels are well studied in literature. However, the localized spatio-temporal effects of the drugs are less well understood. The emergence of spatially preferential drug efficacy of cisplatin and paclitaxel resulting from variations in mechanisms of cell-drug interactions is explored. Using lab-grown 3D spheroids of HeLa-C3 cells and mechanistic model simulations, it is shown that cell repair probability, intracellular drug concentration and cell’s mitosis phase interact to determine the outcomes of drug actions on a local cell population. In spheroids treated with cisplatin, the drug induced apoptosis is found to be scattered throughout the volume of the spheroids. The efficacy of cisplatin is dependent on the stochastic cell repair probability. In contrast, the effect of paclitaxel is found to be preferentially localized along the periphery of the spheroids. The preferential action of paclitaxel can be attributed to the cell characteristics of the peripheral population. Combinatorial treatments of cisplatin and paclitaxel result in varying levels of cell apoptosis in the spheroids based on the scheduling strategy. Treatments initiated with paclitaxel are found to be more efficacious than its counterpart due to the cascading of spatial effects of the drugs. Short time drug alternation strategies produce largely similar treatment outcomes irrespective of the drug ordering. Invadopodia of tumor cells have been sufficiently documented for their role in tumor progression and distant metastasis. Invadopodia formation is found to promote extravasation of circulating tumor cells, which has been verified by different experiment models. The influence of microenvironment on invadopodia formation of circulating tumor cells is largely unknown. The fluidic shear stress, which is an important physiological factor in the microenvironment of circulating tumor cells, is investigated for its effects on invadopodia formation. By utilizing a microfluidic system, shear stress is applied on tumor cells. Shear stress is found to promote invadopodia formation of tumor cells. The mechanism study using biological experiments and Glazier-Graner-Hogeweg method-based numerical model simulations shows that shear stress-generated reactive oxygen species is able to activate tyrosine kinase 5 and enhance invadopodia formation. This study provides insights on the invasiveness of metastatic cells and has important implications for cancer prognosis and therapy development. Ductal carcinoma in-situ (DCIS) presents a risk of transformation to malignant intraductal carcinoma (IDC) of the breast. Three tumor suppressor genes RB, BRCA1 and TP53 are critical in curtailing the progress of DCIS to IDC. The complex transition process from DCIS to IDC involves acquisition of intracellular genomic aberrations and consequent changes in phenotypic characteristics and protein expression level of the cells. There is a lack of proper understanding of the spatiotemporal dynamics associated with breech of epithelial basement membrane and subsequent invasion of stromal tissues during the transition. Therefore, the emergence of invasive behavior in benign tumor, emanating from altered expression levels of the three critical genes is explored in this thesis. A multiscale mechanistic model is used to unravel the phenotypical and biophysical dynamics promoting the invasive nature of DCIS. Ductal morphologies including comedo, hyperplasia and DCIS evolve spontaneously from the interplay between the gene activity parameters in the simulations. The model elucidates the cause and effect relationship between cell-level biological signaling and tissue-level biophysical response in the ductal microenvironment. The model predicts that BRCA1 mutations will act as a facilitator for DCIS to IDC transitions while mutations in RB act as initiator of such transitions. Overall, the three model studies highlight the importance of tumor microenvironment in determining the treatment outcomes and cancer progression. Tumor microenvironment drives the non-linear response of tumor cells to chemotherapy. The studies indicate a heterogenous response to chemotherapy from a genetically homogenous tumor population. The DCIS to IDC transformation study suggests RB as a crucial drug target candidate to prevent tumor growth and arrest further metastases. Similarly, the extravasation study proposes ROS as an external environmental factor promoting cancer cell extravasation and therefore, consequently, a critical drug candidate. Thus, this thesis successfully identifies significant biophysical and chemical targets in the tumor microenvironment landscape which enable evasion and reduction of chemotherapeutic efficacy in cancer treatment.