A computational model of the spatiotemporal adaptation of tumor cells metabolism in a growing spheroid

Abstract

AbstractThe Warburg effect, commonly depicted as an inherent metabolic trait of cancer in literature, is under intensive investigation to comprehend its origins. However, while the prolonged presence of excessive lactic acid production in tumors has been noted, it merely constitutes a fraction of the potential metabolic states cancer cells can adopt. This study aimed to elucidate the emergence of spatiotemporal diversity in tumor energy metabolism by expanding an existing model based on experimental facts. The resulting hybrid model integrates discrete formulations for individual cells and their processes, along with continuous elements for metabolism and the diffusion of crucial environmental substrates like oxygen, glucose, lactate, and the often underestimated acidity. This model enables simulation of a tumor spheroid, a standard experimental model, composed of numerous cells which can have distinct traits. By subjecting the spheroid to alterations of the environment such as cyclic hypoxia, acid shocks, or glucose deprivation, novel insights into metabolic regulation were obtained. The findings underscore the significance of the pyruvate-lactate interaction in governing tumor metabolic routes. Integrating acidity’s impact into the model, revealed its pivotal role in energy pathway regulation. Consequently, the conventional portrayal of a respiration/fermentation dichotomy proves inaccurate, as cells continuously and spatially adjust the ratio of these energy production modes, in contrast to abrupt, irreversible switches. Moreover, a cooperative cellular behavior akin to the reverse Warburg effect has emerged. This implies that the Warburg effect is not universally inherent to tumor metabolism, but a contextual, transient metabolic expression. Ultimately, the dynamic cellular-environment metabolic landscape influences cells’ survival under external conditions, with epigenetic regulations shaping their mobility potential within this landscape. While genetic mutations within tumor cells are undoubtedly present, this study shows they are not invariably essential for extreme metabolic modes or pathological characteristics to arise. Consequently, this research paves the way for innovative perspectives on metabolism, guiding tailored therapeutic strategies that consider not just patient-specific tissue attributes but also treat tumors as intricate ecosystems beyond their genetic diversity.Author SummaryFor years, scientists have been intrigued by the peculiar energy consumption patterns of cancer cells, such as the Warburg effect characterized by excessive lactic acid production. This study aimed to decipher the underlying reasons for the varying energy behaviors observed in different parts of tumors. Using a computational model, we simulated the collaborative dynamics of cells within tumors. The results revealed compelling insights. Two molecules, pyruvate and lactate, were identified as influential players in shaping energy utilization. Remarkably, the surrounding acidity was also found to exert a significant impact. Interestingly, tumor cells display a certain flexibility in their energy production strategies, adjusting according to prevailing conditions to maintain their survival and adaptability. Interestingly, cellular cooperation challenges the Warburg effect as an omnipresent phenomenon and reveals a transient nature. Our study underscores the significance of environmental influences, shedding light on the interplay between genetic modifications and the tumor environment in shaping cellular behavior. These findings hold promise for transforming cancer comprehension and devising treatments that tailor to both patients and the distinctive characteristics of their tumors.