The Tumor Microenvironment Drives Intrahepatic Cholangiocarcinoma Progression

Serena Mancarella, Grazia Serino, Sergio Coletta, Raffaele Armentano, Francesco Dituri, Francesco Ardito, Andrea Ruzzenente, Isabel Fabregat, Gianluigi Giannelli

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review


Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with limited therapeutic options and short overall survival. iCCA is characterized by a strong desmoplastic reaction in the surrounding ecosystem that likely affects tumoral progression. Overexpression of the Notch pathway is implicated in iCCA development and progression. Our aim was to investigate the effectiveness of Crenigacestat, a selective inhibitor of NOTCH1 signaling, against the cross-talk between cancer cells and the surrounding ecosystem in an in vivo HuCCT1-xenograft model. In the present study, a transcriptomic analysis approach, validated by Western blotting and qRT-PCR on iCCA tumor masses treated with Crenigacestat, was used to study the molecular pathways responsive to drug treatment. Our results indicate that Crenigacestat significantly inhibited NOTCH1 and HES1, whereas tumor progression was not affected. In addition, the drug triggered a strong immune response and blocked neovascularization in the tumor ecosystem of the HuCCT1-xenograft model without affecting the occurrence of fibrotic reactions. Therefore, although these data need further investigation, our observations confirm that Crenigacestat selectively targets NOTCH1 and that the desmoplastic response in iCCA likely plays a key role in both drug effectiveness and tumor progression.
Lingua originaleEnglish
pagine (da-a)4187-N/A
Numero di pagine17
RivistaInternational Journal of Molecular Sciences
Stato di pubblicazionePubblicato - 2022


  • Bile Duct Neoplasms
  • Bile Ducts, Intrahepatic
  • Cholangiocarcinoma
  • Ecosystem
  • HuCCT1-xenograft mouse model
  • Humans
  • NOTCH1
  • Tumor Microenvironment
  • gene expression
  • intrahepatic cholangiocarcinoma
  • microenvironment


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