O'Rourke, Colm J. and Salati, Massimiliano and Rae, Colin and Carpino, Guido and Leslie, Holly and Pea, Antonio and Prete, Maria G. and Bonetti, Luca R. and Amato, Francesco and Montal, Robert and Upstill-Goddard, Rosie and Nixon, Colin and Sanchon-Sanchez, Paula and Kunderfranco, Paolo and Sia, Daniela and Gaudio, Eugenio and Overi, Diletta and Cascinu, Stefano and Hogdall, Dan and Pugh, Sian and Domingo, Enric and Primrose, John N. and Bridgewater, John and Spallanzani, Andrea and Gelsomino, Fabio and Llovet, Josep M. and Calvisi, Diego F. and Boulter, Luke and Caputo, Francesco and Lleo, Ana and Jamieson, Nigel B. and Luppi, Gabriele and Dominici, Massimo and Andersen, Jesper B. and Braconi, Chiara (2023) Molecular portraits of patients with intrahepatic cholangiocarcinoma who diverge as rapid progressors or long survivors on chemotherapy. BMJ PUBLISHING GROUP, LONDON.
Full text not available from this repository. (Request a copy)Abstract
Objective Cytotoxic agents are the cornerstone of treatment for patients with advanced intrahepatic cholangiocarcinoma (iCCA), despite heterogeneous benefit. We hypothesised that the pretreatment molecular profiles of diagnostic biopsies can predict patient benefit from chemotherapy and define molecular bases of innate chemoresistance.Design We identified a cohort of advanced iCCA patients with comparable baseline characteristics who diverged as extreme outliers on chemotherapy (survival <6 m in rapid progressors, RP; survival >23 m in long survivors, LS). Diagnostic biopsies were characterised by digital pathology, then subjected to whole-transcriptome profiling of bulk and geospatially macrodissected tissue regions. Spatial transcriptomics of tumour-infiltrating myeloid cells was performed using targeted digital spatial profiling (GeoMx). Transcriptome signatures were evaluated in multiple cohorts of resected cancers. Signatures were also characterised using in vitro cell lines, in vivo mouse models and single cell RNA-sequencing data.Results Pretreatment transcriptome profiles differentiated patients who would become RPs or LSs on chemotherapy. Biologically, this signature originated from altered tumour-myeloid dynamics, implicating tumour-induced immune tolerogenicity with poor response to chemotherapy. The central role of the liver microenviroment was confrmed by the association of the RPLS transcriptome signature with clinical outcome in iCCA but not extrahepatic CCA, and in liver metastasis from colorectal cancer, but not in the matched primary bowel tumours.Conclusions The RPLS signature could be a novel metric of chemotherapy outcome in iCCA. Further development and validation of this transcriptomic signature is warranted to develop precision chemotherapy strategies in these settings.
| Item Type: | Other |
|---|---|
| Uncontrolled Keywords: | BILIARY-TRACT CANCER; THERAPEUTIC TARGETS; LIVER METASTASIS; OPEN-LABEL; MULTICENTER; GEMCITABINE; PHASE-3; chemotherapy; liver; cholangiocarcinoma |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 07 May 2024 06:28 |
| Last Modified: | 07 May 2024 06:28 |
| URI: | https://pred.uni-regensburg.de/id/eprint/60903 |
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