Loss of Dkk3 promotes stemness and migration in primary pancreatic cancer cells
RefereeHermann, Patrick C.
InstitutionsUKU. Klinik für Innere Medizin I
UKU. Institut für Pathologie
Pancreatic cancer still remains a terrifying and deadly disease. While several key regulators and pathways have been elucidated to bring a better understanding and to provide a basis for therapeutic approaches, studies addressing pancreatic ductal adenocarcinoma (PDAC) and possible therapeutic targets are as important as ever. We focused on the Dickkopf-Protein 3 (Dkk3), a natural Wnt modulator and investigated its role in primary pancreatic cancer cells. It has been shown that Dkk3 plays an important role for cancer and tumorigenesis in general. Recent studies confirmed that it plays an essential role in PDAC as well, but the data available in the literature is conflicting. As the scientific focus of our group is the study of cancer stem cells, we used genetic interference to perform shRNA-mediated knockdown of Dkk3 and then analyze the effects on the cancer stem cell (CSC) population. In this study we tried to elucidate whether Dkk3 plays an important functional or regulatory role in primary pancreatic cancer stem cells. In summary, our results are very promising: the loss of DKK3 resulted in a significantly enhanced cancer stem cell population. While no enhanced stemness signature was detectable when looking at gene expression, there was a significant increase in CD133+ cancer stem cells in primary pancreatic cancer cells. Even more importantly, functional analyses such as sphere formation, migration and invasion assays confirmed a significantly enhanced CSC population after DKK3 knockdown. Since there still is no perfect surface marker combination to identify single CSCs, (and therefore CSCs are still defined operationally by functional features) these findings clearly support the influence of DKK3 loss on pancreatic cancer stem cells. Since CSCs are usually a small subpopulation within a tumor, gross changes in cell proliferation or changes in gene expression were not to be expected. Altogether, we can conclude that the loss of DKK3 promotes a cancer stem cell phenotype in primary pancreatic cancer cells. The detailed regulatory mechanism to achieve this, however, is unclear at present and will be the subject of further studies. An important aspect for further studies on the influence of Dkk3 on the regulation of cancer (stem) cells will be to consider the strong influence of the stroma and of stroma-CSC cross-regulation.
Subject headings[GND]: Krebs <Medizin> | Bauchspeicheldrüsenkrebs | Stammzelle
[MeSH]: Pancreatic neoplasms | Neoplastic stem cells | Wnt signaling pathway | Stem cells | Cell movement
[Free subject headings]: Tumorstammzelle | Migration | Invasion | Dickkopf-Protein 3
[DDC subject group]: DDC 610 / Medicine & health
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DOI & citation
Please use this identifier to cite or link to this item: http://dx.doi.org/10.18725/OPARU-38059