Basic Biology V
$1 161 000
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.
Statement of Benefit to California:
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.
Tumors contain a broad mix of cancer cells with distinct features that include a subset of particularly aggressive cancer stem cells. Since a single cancer stem cell can self-renew, divide, migrate and differentiate, the ability of one cell to evade targeted therapies or surgical resection can lead to tumor re-growth and disease relapse. The goal of the proposed study is to study the role of a cancer stem cell surface protein (CD61) in the progression of cancer. The proposed project was designed to evaluate the use of CD61 as a marker for tumors and further evaluate the role of CD61 in giving cancer cells stem-cell-like properties. The investigators will focus on the role of extracellular molecular interactions with CD61, and the consequence cell signaling. Further, the investigators will use signals that disrupt the CD61 pathway in an effort to reverse the observed “stemness” effects. The information gained from this study may be useful for developing intervention-based therapies aimed to reduced the activity of cancer stem cells tumors, with the ultimate goal of finding a more effective treatment for cancer. Significance and Innovation - This application is a novel and innovative approach that could provide a means of identifying and targeting human cancer stem cells and would help validate CD61 as a marker for cancer “stemness”. - As such, the outcomes from these studies would be significant and provide important insights into the mechanisms underlying the up-regulation of CD61. - Determining the roles and influences of downstream molecular interactions could be highly significant and contribute to the development of new cancer treatment strategies. - One of the concerns expressed by reviewers was related to the idea that the proposal appeared to be more related to cancer than to stem cells. Feasibility and Experimental Design - The proposal is supported by an extensive background of information and is grounded on sound science. - The proposed experimental design is logical, will provide the ability to accomplish the aims/objectives, and is therefore feasible to accomplish. - There appeared to be consensus that the study represented a novel and promising line of research. Principle Investigator and Research Team - The PI has the appropriate background, expertise and publishing background to successfully oversee/complete the proposed studies. However, there was some concern noted that the PI may not have a sufficient amount of time available for the project - The research team and other contributors have the appropriate expertise and experience to conduct the proposed research. Responsiveness to the RFA - Overall the work is exciting, holds much potential for significant results, and is highly responsive to the RFA. The aims are geared toward understanding the role of a cell surface protein found in cancer stem cells, and how this protein gives the cells “stem-cell-like” properties.