Targeting Cripto in Breast Cancer Plasticity
Abstract
Breast cancer remains the second-leading cause of death from cancer among women. Although treatments for breast cancers continue to improve, many patients will exhibit disease progression involving therapy resistance, recurrence, and the dissemination of breast cancer cells to form life-threatening tumors in distant organs, a process known as metastasis. Cells responsible for the various steps of breast cancer progression need to be plastic, i.e., able to change and adapt to challenging environments. However, not enough is known about tumor cell plasticity and which genes and proteins are essential in the process. Our project aims to investigate the role of the cellular proteins CRIPTO and GRP78 in promoting breast cancer cell plasticity and metastasis, and will test if specifically blocking their cooperative signaling at the tumor cell surface has therapeutic potential, as our preliminary studies in a mouse model of human breast cancer suggest. Our preliminary work indicates that CRIPTO blockade will be helpful in treating triple-negative breast cancers (TNBC), but we hypothesize and will test whether it also has application in treating diverse subtypes beyond TNBC, as there is some evidence for this also. CRIPTO is a small protein that is exposed at the surface of cells or secreted into the extracellular space between cells. Breast cancers contain abnormally high levels of CRIPTO and prior studies including our own have demonstrated that when CRIPTO binds to GRP78 on the surface of cells of the breast, it can block normal cellular differentiation and promote cellular plasticity. Recently, we developed a CRIPTO-binding decoy receptor called ALK4m-Fc that can interact with CRIPTO outside the cell before it is able to bind GRP78 and initiate the signaling process. Our studies will assess how increasing CRIPTO levels or decreasing CRIPTO activity with ALK4m-Fc and related agents affects breast cancer cell plasticity and cellular behaviors important for breast cancer progression. We will examine how the specific environment surrounding select cancer cells may promote CRIPTO signaling and determine which molecular signaling pathways cooperate in this activity. Importantly, we will examine the ability of CRIPTO blockade to inhibit tumor growth and disease progression in mice and relate these findings to human disease. The proposal has the long-term potential to address all of the stated overarching challenges identified in the BCRP funding opportunity announcement. This is because it proposes to elucidate the role of a signaling pathway (i.e., the CRIPTO/GRP78 pathway) that has not been previously studied in the specific subpopulations of stem cell-like cells across the diversity of breast cancers and has not been analyzed for its molecular role in their adaptation to cancer associated stresses. In fact, few if any adaptive, stem cell- and plasticity-promoting molecular mechanism in these cells, which we refer to as tumor-propagating cells, have been directly studied or effectively targeted, though such cell responses may be critical during treatment and at other critical stages of the disease. Furthermore, upon completion of our proposed studies, we expect that CRIPTO-blocking agents like ALK4m-Fc could be entered into the clinical studies pipeline and become available to patients in the near future, providing an important modality for tackling the most difficult aspects of breast cancer treatment, i.e., cellular plasticity and adaptation. Though we believe the proposal has impact on all of the indicated overarching challenges, it most immediately addresses the challenges of: 1) Revolutionizing treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. - We propose to identify synergistic therapies involving Cripto/GRP78 pathway disruption that may allow reduction in the dose of standard chemotherapies, many of which have associated toxicities while at the same time increasi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110802
Entities
People
- Bryan Welm
Organizations
- United States Army
- University of Utah