The Self-Replication of Cancer Cells
Cancer cells hijack stem cell self-renewal mechanisms by acquiring mutations that overactivate these pathways. By comparing the mechanisms that regulate the self-renewal of normal stem cells and the self-replication of cancer cells, we identify differences that represent potential vulnerabilities that can be targeted to kill cancer cells. For example, ion gradients are rarely studied in cancer cells. However, we have discovered that the ability of cancer cells to maintain subcellular ion gradients appears to be persistently stressed and that inhibitors of ion transporters can have synthetic lethal effects when combined with targeted agents that inhibit oncogenic signaling pathways.
We are particularly interested in the mechanisms that regulate melanoma metastasis. We have discovered that the distant metastasis of melanoma cells is limited by high levels of reactive oxygen species that arise in melanoma cells during metastasis. Our data suggest that this causes oxidative stress that kills the vast majority of melanoma cells as they attempt to metastasize, potentially explaining why distant metastasis is such an inefficient process. The rare cells that successfully metastasize appear to undergo metabolic changes that enhance their capacity to cope with oxidative stress. Our results suggest that rather than treating cancer with antioxidants, we should be treating with pro-oxidants that exacerbate oxidative stress or that inhibit the ability of cancer cells to metabolically adapt.