Characterization of stem-like circulating tumor cells for metastasis treatment and generation of circulating tumor cells-derived xenograft models for translational and preclinical studies

Project: Research project

Project Details

Description

Breast cancer is the most common cancer in women worldwide. In the US, it is the second diagnosed cancer among American women; about 1 in 8 (about 12%) women will develop invasive breast cancer over the course of their lifetimes. Among them, metastasis is a major cause of cancer-related mortality. Circulating tumor cells (CTCs) are cells shed from primary tumors and circulate in the peripheral blood. They are considered the seeds of metastasis. However, CTCs are heterogeneous, with less than 0.01% of the CTCs can form the metastasis [1]. One mechanism to explain this inefficiency is provided by the cancer stem cell (CSC) theory, which proposes that only cells with CSC properties can establish metastasis. However, clinical evidence is lacking on the existence of stem-like CTCs with the metastasis-initiating ability in cancer patients. Identification of the stem-like population of CTCs and understanding the clinical correlation of this population with patient outcome and treatment response are critical to discover novel biomarkers and efficient personalized therapeutic strategies for metastatic cancer patients. Previous studies and our preliminary data indicated that clusters of multiple CTCs possess 50 times higher metastatic capacity in mouse breast cancer models, and the presence of CTC clusters is associated with poor diagnosis [2-4]. We also found that CSC marker CD44 is enriched in CTC clusters, suggesting that higher metastatic potential of CTC clusters might be related to stemness. In addition, our preliminary data demonstrated that EGFR is involved in CD44-mediated cell clustering, and active EGFR (phosphorylated EGFR, p-EGFR) localizes at nucleus in the invasive front of tumor and metastatic sites. However, the clinical value of nuclear p-EGFR and its relationship with CD44 and stemness are largely unknown. Based on previous studies and our preliminary data, we will identify the stem-like population in CTCs with particular interests in CTC clusters, and their correlation with patient’s outcome and treatment response. The stemness of identified CTCs will be confirmed by successfully generating CTC-derived patient-derived-xenografts (PDX) mouse models. We will pursue the following three aims in this proposal with the long-term goal to use CTC stemness as a predictive biomarker for cancer patient’s outcome and develop efficient therapeutics for personalized medicine. Specific Aim1: Identify the stem-like subpopulation in CTCs, and determine the clinical correlation of this population with patient outcome and treatment response. Specific Aim2: Determine the co-expression of EGFR with CSC markers, and clinical significance of nuclear localization of p-EGFR in CTCs. Specific Aim3: Generate CTC-derived PDX models in NSG mice to confirm the stemness of identified CTCs, and provide platform for translational and preclinical studies.
StatusFinished
Effective start/end date9/29/179/29/19

Funding

  • AbbVie Inc. (Agmt 9/29/17)

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