Purpose: Patients with pancreatic ductal adenocarcinoma (PDAC) may show an initial objective response to chemotherapy that is usually of short duration. Our research goal is to understand the molecular mechanisms for this short duration response and to more fully define differences between chemosensitive and chemoresistant cells. Cancer cells that undergo an EMT and metastatic tumors show an increase in CD44s expression. In this study, we use CD44 Low and CD44 High isogenic cell models to identifying key molecular networks and potential targets that could benefit therapy.

Experiments design: CFPAC1-CD44 Hi and Low cells were sorted by flowcytometry and single clone selection. Isogenic model systems were generated by overexpression CD44s in CF-Low cells. Western blot, MTT, migration and invasion assays had been used to characterize cell growth, invasiveness and gemcitabine sensitivity. Receptor Tyrosine Kinase arrays were used to identify the CD44 regulated molecular networks in these isogenic cell models treated with/without CD44 ligand hyaluronan acid (HA).

Summary: CD44s high cells show an EMT phenotype (increase of vimentin and loss of E-cadherin) and increase invasion. Expression of CD44s in CD44 low cells was sufficient to drive EMT partially and drive invasion. By in vitro testing over expressing CD44s is not sufficient to decrease sensitivity to gemcitabine. By Receptor Tyrosine Kinase arrays, CD44 Hi clone cells show increase in IGF-1R phosphorylation. Preliminary data had shown that HA may stimulate ROR2, VEGFR1, and EphB2 phosphorylation in CD44 Hi clone cells.

Conclusion: Our previous study suggested that CD44 could be a therapeutic target in Gemcitabine resistant PDAC cells. The current study will further identify the molecular targets that regulated by CD44 pathways. These newly identified targets could be hopefully used for the optimized multimodality therapy to sensitize the PDAC cells to therapy and to benefit the pancreatic cancer patients.

Citation Format: Chen Chen, Shujie Zhao, Xiangru Zhao, James W. Freeman. Role of CD44 as a regulator of adaptive plasticity in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4166. doi:10.1158/1538-7445.AM2017-4166