UC Irvine

The Wnt signaling pathway is a highly conserved cell-to-cell communication network in animals, and it regulates many gene programs essential for organism growth and development. Dysregulation of the Wnt pathway is a characteristic of many diseases, the most recognized of which is cancer. In colon cancer, Wnt-activating mutations are a key initiator of tumorigenesis, and in vitro and in vivo experiments have suggested that targeting the pathway will effectively decrease tumor burden. Despite this, years of clinical trials using Wnt pathway inhibitors in colon cancer patients have not yielded any success. As the push to develop Wnt-targeting therapies continues, a growing body of work points to a more complex understanding of Wnt signaling in colon cancer. In spite of the Wnt-activating mutations, Wnt signaling activities vary widely within a tumor, suggesting additional regulation beyond the constitutive activation. This dissertation presents two consequences of Wnt heterogeneity; first the regulation of cellular metabolism, and second, the regulation of cell migration and invasion.

Our first story builds upon our earlier work, which demonstrated that Wnt directly regulates the expression of glycolytic metabolism genes PDK1 and MCT1. We find that observations of Wnt signaling heterogeneity in tumors are also manifest as heterogeneous metabolism. We show that the spatial patterns of Wnt and metabolic heterogeneity are directly linked and a result of cell-to-cell signaling. This heterogeneity supports growth through efficient distribution of nutrients and proliferative signaling throughout the tumor. We demonstrate that this relationship between Wnt signaling and metabolism can be exploited therapeutically using a combination of Wnt and glycolysis inhibitors.

In the second story, we study heterogeneity in Wnt signaling levels over time, to show that a decrease in Wnt signaling primes tumor cells for invasion. By modulating the level of Wnt signaling in different ways, we show a graded increase of cell invasion and migration with decreasing Wnt levels, in both cell culture and orthotopic tumor models. Using sequencing data from Wnt-decreased cells and colon cancer patients, we identify potential drivers of this invasive phenotype, and suggest their use as therapeutic or diagnostic targets in colon cancer patients advancing to metastatic disease.