Year 1

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 defined a common subset of cancer stem cell features that are induced by CD61 in response to multiple types of cellular stress. These stresses represent those that a tumor cell might encounter within its microenvironment, including nutrient deprivation, hypoxia, or cancer therapy. Interestingly, we have also discovered that these changes are reversible and that tumor cells can be “primed” to respond to stress so that they can rapidly adopt the stem-like features to evade the effects of therapy.

We have also identified specific upstream drivers required for the induction of CD61 by stress, and we have shown that they are necessary and sufficient to trigger CD61. In addition, we are beginning to understand how CD61 orchestrates the conversion of an epithelial cancer cell into a stem-like cancer cell by altering the location and function of downstream signaling proteins. Work in the upcoming year will focus on identifying specific steps along the pathway that could be manipulated therapeutically to prevent this reprogramming of cancer cells that contributes to drug resistance and disease progression.