Year 2

Cancers are often treated based on their underlying disease phenotype or molecular drivers. While these targeted strategies may provide some initial benefit, they tend to fail over time as tumors develop resistance mechanisms. Cancer stem cells, traditionally defined as a small population of “pre-existing” cells responsible for initiating a tumor, have been implicated as a major contributor to drug resistance. Although small in number, it is thought the population of cancer stem cells within a tumor could survive therapy to regenerate an entire tumor over time or spread to distant sites.

We suggest an alternate scenario in which any cell within a tumor could be “converted” into a cancer stem-like cell. We have now demonstrated that exposing epithelial cancer cells to different types of stress, including cancer therapies, induces a subset of markers and functions attributed to traditional cancer stem cells. The goal of our project is to understand how a protein called CD61 drives this reprogramming event so that we can design approaches to interfere with this pathway in order to lock cancer cells into a less aggressive and more therapy-responsive state.

In the past year, we have determined how stress triggers certain changes of the CD61 gene promoter region to allow for the induction of CD61 gene expression. As such, we have now identified specific ways to impede this process to prevent the induction of CD61 and its ability to drive stem reprogramming. We have also identified a mechanism by which CD61 forms clusters on the surface of cancer cells to drive its downstream signaling pathway, and these can also be disrupted to prevent the conversion toward a cancer stem cell phenotype. Lastly, we have begun to identify which downstream signaling mediators are selectively triggered by this pathway, providing additional opportunities to disrupt the reprogramming of epithelial cancer cells.

Work in the upcoming year will focus on testing and validating agents that can disrupt specific steps along the pathway to prevent the CD61-mediated reprogramming of cancer cells that contributes to drug resistance and disease progression.