UC Irvine

Cancer is one of the deadliest diseases; vast resources have been used to understand its root causes and to elucidate the intricacies of cancer progression in order to develop effective prevention and treatment strategies. Unfortunately, there are a lot of factors in the tumor microenvironment that contribute to cancer development and progression. Consequently, a better understanding of the tumor niche has become an important goal of cancer research. Here we have approached the problem using a combination of in vitro assays and computational modeling. Firstly we studied extracellular matrix (ECM).

Recently, it has been found that the ECM surrounding tumors has significant effects on tumor cell growth and migration. However, there is a shortage of information on how cells respond to normal vs tumor ECM. In order to overcome this problem, we have isolated human tumor ECM (tECM) and compared its chemical and mechanical properties to ECM derived from matched normal tissue (nECM). We next examined the ability of each of these matrices to support the development of new vasculature – a key event in tumor progression. We found that the capillaries that form in the tECM have

characteristics similar to those seen in in vivo tumors. We also found that tumor growth and tumor metabolism is different in these two ECMs, with tumor growth being faster, and tumor cell metabolism more glycolytic, in the tECM. Taken together, these data identify the importance of the ECM in tumor progression and suggest that normalization of ECM morphology and composition could provide a novel strategy to limit tumor growth.

Our second approach used mathematical models to study the interaction of different tumor cell lineages with the vascular niche. We find evidence to support the idea of endothelial cell transdifferentiation into tumor cells. And, the computational simulations of the model indicated that the transdifferentiated glioblastoma cells to have a major contribution in tumor therapy resistance.