XCT and CD44v9 Co‐Expression Mediates Pancreatic Ductal Adenocarcinoma Survival in the Presence of ROS Inducing Chemotherapeutics

Abstract

BackgroundPancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer‐related death in the United States. It has been shown that KRAS mutations, often found in PDAC, can lead to the up‐regulation of the expression of the cysteine/glutamate transporter xCT. Transporter xCT has been shown to allow cancer cells to evade ROS mediated cell death. CD44 is a transmembrane protein with many different splice varients. CD44 variant isoform 9 (CD44v9) is expressed during cellular damage and has been shown to mediate cell survival. CD44v9 stabilizes xCT expression on the surface of cancer cells. Therefore, CD44v9 stabilized the xCT transporter, which allows cancer cells to survive following treatment with chemotherapeutics that induce ROS.HypothesisTransporter xCT and CD44v9 co‐expression mediates PDAC survival in the presence of ROS inducing chemotherapeutics.MethodsHuman‐derived pancreatic cancer organoids (HuTPOs) were generated from the resected tissue of patients with PDAC. A dose response curve was performed by treating the huTPOs with eight different micromolar concentrations of oxaliplatin, gemcitabine, 5‐fluorouracil (5‐FU). These chemotherapeutics have been shown to induce ROS within PDAC cells. The susceptibility or resistance of the huTPOs to the chemotherapeutics was determined by measuring cell death by an MTS proliferation assay. HuTPOs were analyzed by immunofluorescence for the expression of the cysteine‐glutathione transporter, xCT, and cancer stem cell marker, CD44v9.ResultsThere was divergent expression of xCT and CD44v9 in huTPO lines generated from individual patients. Dose response curves performed on huTPO lines revealed that organoids not expressing xCT or only xCT were sensitive to ROS inducing chemotherapeutics (5‐FU, oxaliplatin and gemcitabine). Interestingly, huTPOs that expressed both xCT and CD44v9 were resistant to 5‐FU, oxaliplatin and gemcitabine.ConclusionCD44v9 may stabilize xCT in PDAC cancer organoids allowing for resistance to ROS inducing chemotherapeutics. Pancreatic organoids may be a good screening based model to determine efficacy of ROS inducing chemotherapeutics in PDAC.Support or Funding InformationSteven Goldman Memorial Pancreatic Cancer Research Grant (Zavros) 1RO1DK083402This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.