CD61-driven stemness program in epithelial cancer
Tumors contain a heterogeneous mix of cancer cells with distinct features, including subsets of particularly aggressive stem-like cells. Since a single cancer stem cell can self-renew, divide, and differentiate to reconstitute the heterogeneity of an entire tumor, the ability of one cell to evade therapy or surgical resection could lead to tumor re-growth and disease relapse.
Few, if any, individual markers have been capable of identifying cancer stem cells among distinct tumor types. It is therefore remarkable that we have detected enrichment of CD61 on stem-like cells within tumor biopsies from many different drug-resistant samples of lung, breast, pancreatic, and brain tumors from mice or humans.
CD61 promotes a stem-like reprogramming event, since ectopic expression CD61 induces stemness, including self-renewal, tumor-forming ability, and resistance to therapy. CD61 drives these behaviors by activating a signaling pathway which can be inhibited to reverse stemness and sensitize tumors to therapy.
Our project is focused on learning how CD61 drives this cancer stem cell program, and how the increase in CD61 could be prevented or reversed. If successful, our work will provide valuable new insight into a cancer stem cell program that is unexpectedly shared among a variety of solid tumor types.
The American Cancer Society estimates 171,330 new cancer cases will be diagnosed in California this year, a 10th of the national total. As part of an NCI-designated comprehensive cancer, we are uniquely positioned to translate our basic science research into clinical impact for the cancer patients within our community.
From a clinical perspective, the understanding gained from our proposed studies will broadly benefit patients in California who will be diagnosed with an epithelial cancer this year, including 25,360 new breast cancer patients and 18,720 new lung cancer patients. Gaining fundamental insight into how these cancers are reprogrammed to become more stem cell-like as they acquire resistance to therapy will facilitate development of new strategies to prevent or reverse this behavior to benefit these large numbers of patients who live in California. In addition, our work will also yield new diagnostic tools that could identify which patients might respond to certain therapies.
At the basic science level, our project will also serve to elucidate the mechanisms by which cancer stem cells contribute to cancer progression and response to therapy. During the course of our project, we will be able to train more people in California to work on this cutting-edge research, and to establish a foundation for the logical design of anti-cancer therapies targeting this unique cancer stem cell population.
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.