Project FP 15-08. The Dutch Digestive Foundation (MLDS)

EpCAMlow cancer stem cells: the culprit of liver metastasis in colon cancer?

Andrea SacchettiMiriam Teeuwssen, Mathijs Verhagen

To form metastasis in distant organs, cancer cells need to detach from the primary tumor, migrate through stromal layers, intra- and extravasate blood and lymph vessels, and eventually colonize distant organs. One essential feature of the successful metastatic cell is plasticity, i.e. the stem-like capacity to respond to external cues by altering its own cellular identity through the so-called epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions (EMT and MET). EMT implies a reversible loss of epithelial characteristics in favour of more mesenchymal ones and represents the main mechanism underlying dissemination and metastasis of cancer cells. Strikingly, most of the studies on circulating tumor cells (CTCs) in peripheral blood of cancer patients have been limited to cells expressing the epithelial marker EpCAM. While these studies demonstrated the prognostic value of CTCs, they fail to identify the cells that drive metastasis as these are likely to have lost their epithelial features (and EpCAM expression).
Here, we aim at the isolation and functional characterization of the migrating cancer stem cells (mCSCs) which underlie tumor cell dissemination and liver metastasis in colon cancer.
To this aim, we recently identified a small subpopulation of EpCAMlo cells in colon cancer cell lines. These cells have undergone EMT and show enhanced invasive and metastatic capacity both in vitro and in vivo. Notably, EpCAMlo cells are resistant to chemotherapy. Here, we aim at the characterization of these EpCAMlo cells including expression profiling, lineage tracing in preclinical mouse models, their validation as CTCs in colon cancer patients, and their therapeutic targeting.
Anticipated results:
The results of our study will lead to the identification and functional characterization of a novel class of stem-like CTCs in colon cancer which will serve as novel diagnostic and prognostic tools, and as the main targets of tailor-made therapies.


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