Abstract
Many tumors are characterized by genetic instability, producing an assortment of genetic variants of tumor cells called subclones. These tumors and their surrounding environments form complex multi-cellular ecosystems, where subclones compete for resources and cooperate to perform multiple tasks, including cancer invasion. Recent empirical studies revealed existence of such distinct phenotypes of cancer cells, leaders and followers, in lung cancer. These two cellular subclones exchange a complex array of extracellular signals where interplay between them demonstrates a symbiotic relationship at the cellular level. Here, we develop a computational model of the microenvironment of the lung cancer ecosystem to explore how the relationships between subclones can advance or inhibit cancer progression. We found that due to the complexity of the ecosystem, cancer growth may have very different dynamics characterized by the different levels of aggressiveness. By altering the signaling environment, we could alter the ecological relationship between the cell types and the overall dynamics of the cancer cells population. Specifically, inhibition of the feedbacks targeting leader type of the cancer cells had profound impact on the outcome of cancer growth. Our study predicts a complex division of labor between cancer cell subclones and suggests new treatment strategies targeting signaling within heterogeneous tumor cell populations.
Footnotes
Supported by: R01DC012943 (MB), R01CA142858 (AIM), R01CA194027 (AIM), R01CA201340 (AIM). SH is Postdoctoral Kirschstein-NRSA fellow supported by training award T32HL134632.