Two subpopulations of pancreatic adenocarcinoma (PDAC) cells were separated from different cell lines on the basis of CD44 expression level. CD44 high and CD44 low expressing cells were compared for their invasive potential, epithelial/mesenchymal phenotype, in vitro response and in vivo development of resistance to gemcitabine. CD44 high cells showed a mesenchymal phenotype, formed tumor spheres, were more invasive and were less responsive to gemcitabine. In contrast, CD44 low cells had an epithelial phenotype, were weakly invasive, did not grow as tumor spheres and showed greater response to gemcitabine. CD44 high cells showed a predominant expression of CD44 standard isoform with lower levels of various CD44 variant isoforms. Interestingly, gemcitabine treatment of CD44 low cells induced a phenotypic switch, loss of ESRP1 expression with concurrent up regulation in expression of CD44 standard. In an orthotopic mouse model, tumors from CD44 high cells had a selective growth advantage and formed metastases more rapidly. Gemcitabine treatment continuously suppressed tumor growth in animals implanted with CD44 low cells during the 22 weeks of the experiment; whereas, tumors from CD44 high cells initially showed some response to gemcitabine but developed resistance by weeks 10-12. Knockdown of CD44 in CD44 high cells from two different PDAC cell lines, inhibited invasion and increased their response to gemcitabine similar to that seen for CD44 low cells. Collectively this study suggests that a subpopulation of CD44 high expressing PDAC cells with a mesenchymal-like phenotype tends to be highly invasive, more resistant to gemcitabine in vitro and to develop gemcitabine resistance in vivo. Thus, initial targeting CD44 or reversing the CD44 high phenotype may improve therapeutic response of PDAC.

Citation Format: James W. Freeman, Shujie Zhao, Chen Chen, Anand Karnad.{Authors}. Role of CD44 in pancreatic cancer cell plasticity. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B68.