University Training Consortium (CTAC - Trauma)

Breast cancer is the most common cancer among women in the United States, and triple-negative breast cancer (TNBC) is more aggressive than other breast cancer subtype. Metastasis, a stage of breast cancer where the tumor cells have released from the breast and travel to other organs in the body, is responsible for the vast majority of breast cancer deaths. Therefore, it is critical and urgent to find the effective treatment to inhibit metastasis. To metastasize, cancer cells have to enter into the bloodstream, in which they are called “circulating tumor cells” (CTCs). Since repeated tissue biopsies are invasive, costly and not always feasible, the CTCs analysis by a peripheral blood sample as a 'liquid biopsy', represents an attractive opportunity to improve cancer diagnosis and treatment. In our previous studies, we have found that CTCs clusters with two or more individual CTCs bound together have greater metastatic potential than single CTCs, and the presence of CTC clusters having CD44 protein is associated with shorter survival of patients. Our recent study further indicated that cleavage of CD44 protein is involved in CTC-cluster formation. Given that the enzyme ã-secretase is responsible for CD44 cleavage, we aim to test whether ã-secretase inhibitors can inhibit metastasis by blocking CD44 cleavage and CTC cluster formation, in the hope of approving that CTC clusters having CD44 protein can serve as a treatment selection marker for ã-secretase inhibitors. The success of this project will discover a more precise and effective treatment for metastatic TNBC. Scientific Project Summary (technical language) Circulating tumor cells (CTCs) are considered as “seeds of metastasis”. The analysis of CTCs offers new opportunity to discover new mechanism of cancer metastasis and new liquid biomarkers, and can lead to the development of novel anti-metastatic therapeutics. Compared to single CTCs, multicellular aggregates of CTCs (CTC clusters) possess higher metastatic capacity. Our previous studies further indicated that CD44 mediates CTC aggregation and aggregated CD44+ triple negative breast cancer (TNBC) cells have enhanced metastatic ability in mouse models. Importantly, the presence of CD44+ CTC clusters correlates with a poor prognosis of breast cancer patients. We recently found that expression of CD44 intracellular domain (CD44 ICD), which is generated from the cleaved CD44 by ã-secretase, was increased during cell aggregation. Therefore, we hypothesize that cell aggregation activates ã-secretase, which then induces CD44 cleavage and release CD44 ICD. Since it is known that CD44 ICD can promote stemness and tumorigenesis, we aim to determine the role of CD44 ICD in TNBC metastasis (Aim1). Given that ã-secretase inhibitors (GSIs) are being actively repurposed as anti-cancer drugs, we will also determine the efficacy of GSIs in CD44-mediated CTC cluster formation and metastasis in preclinical TNBC mouse models (Aim2). The final goal of this innovative translational exploratory study is to test the feasibility of targeting CD44-mediated CTC cluster formation to inhibit metastasis by GSIs in mouse models, which provides the preclinical evidence to repurpose GSIs for the individualized treatment of metastatic TNBC patients with CD44+ CTC clusters.