Deletion of the mRNA stability factor ELAVL1 (HuR) in pancreatic cancer cells disrupts the tumor microenvironment integrity. Issue 2 (19th April 2023)

• Record Type: Journal Article
• Authors: McCarthy, Grace A; Di Niro, Roberto; Finan, Jennifer M; Jain, Aditi; Guo, Yifei; Wyatt, Cory R; Guimaraes, Alexander R; Waugh, Trent A; Keith, Dove; Morgan, Terry K; Sears, Rosalie C; Brody, Jonathan R
• Is Part Of: NAR cancer. Volume 5:Issue 2(2023)
• Publication Date: 2023-04-19
• Subjects: Cancer -- Periodicals; Cancer -- Genetic aspects -- Periodicals; Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 616.994
• DOI: 10.1093/narcan/zcad016
• Languages: English
• ISSNs: 2632-8674

Abstract

Abstract: Stromal cells promote extensive fibrosis in pancreatic ductal adenocarcinoma (PDAC), which is associated with poor prognosis and therapeutic resistance. We report here for the first time that loss of the RNA-binding protein human antigen R (HuR, ELAVL1 ) in PDAC cells leads to reprogramming of the tumor microenvironment. In multiple in vivo models, CRISPR deletion of ELAVL1 in PDAC cells resulted in a decrease of collagen deposition, accompanied by a decrease of stromal markers (i.e. podoplanin, α-smooth muscle actin, desmin). RNA-sequencing data showed that HuR plays a role in cell–cell communication. Accordingly, cytokine arrays identified that HuR regulates the secretion of signaling molecules involved in stromal activation and extracellular matrix organization [i.e. platelet-derived growth factor AA (PDGFAA) and pentraxin 3]. Ribonucleoprotein immunoprecipitation analysis and transcription inhibition studies validated PDGFA mRNA as a novel HuR target. These data suggest that tumor-intrinsic HuR supports extrinsic activation of the stroma to produce collagen and desmoplasia through regulating signaling molecules (e.g. PDGFAA). HuR-deficient PDAC in vivo tumors with an altered tumor microenvironment are more sensitive to the standard of care gemcitabine, as compared to HuR-proficient tumors. Taken together, we identified a novel role of tumor-intrinsic HuR in its ability to modify the surrounding tumor microenvironment and regulate PDGFAA. Graphical Abstract: