Molecular portraits of patients with intrahepatic cholangiocarcinoma who diverge as rapid progressors or long survivors on chemotherapy

O’Rourke, C. J. et al. (2023) Molecular portraits of patients with intrahepatic cholangiocarcinoma who diverge as rapid progressors or long survivors on chemotherapy. Gut, (doi: 10.1136/gutjnl-2023-330748) (PMID:37758326) (Early Online Publication)

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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:Articles
Additional Information:This work was performed under the frame of the European Network for the Study of Cholangiocarcinoma (ENSCCA) and the COST Action Collaboration (COST Action CA18122 European Cholangiocarcinoma Network Euro-Cholangio-Net). S:CORT was funded by a UK Medical Research Council (MRC) Stratified Medicine Consortium programme grant (MR/M016587/1) with support also from Cancer Research-UK. New EPOC was also supported by Cancer Research-UK. This work was supported by the CRUK Scotland Centre [grant number 100006].
Status:Early Online Publication
Glasgow Author(s) Enlighten ID:Jamieson, Professor Nigel and Rae, Dr Colin and Prete, Mrs Maria Giuseppin and Braconi, Professor Chiara and Leslie, Ms Holly and pea, Dr Antonio and Upstill-Goddard, Dr Rosie and Amato, Francesco and Sanchon-Sanchez, Miss Paula
Authors: O’Rourke, C. J., Salati, M., Rae, C., Carpino, G., Leslie, H., Pea, A., Prete, M. G., Bonetti, L.R., Amato, F., Montal, R., Upstill-Goddard, R., Nixon, C., Sanchon-Sanchez, P., Kunderfranco, P., Sia, D., Gaudio, E., Overi, D., Cascinu, S., Hogdall, D., Pugh, S., Domingo, E., Primrose, J. N., Bridgewater, J., Spallanzi, A., Gelsomino, F., Llovet, J.M., Calvisi, D. F., Boulter, L., Caputo, F., Lleo, A., Jamieson, N. B., Luppi, G., Dominici, M., Andersen, J. B., and Braconi, C.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Gut
Publisher:BMJ Publishing Group
ISSN (Online):1468-3288
Published Online:27 September 2023
Copyright Holders:Copyright © Author(s) (or their employer(s)) 2023
First Published:First published in Gut 2023
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
315305Dissecting the transcriptomic and phenotypic reprogramming of monocytes that mediate chemoresistance in cholangiocarcinoma.Chiara BraconiOffice of the Chief Scientific Adviser (CSO)TCS/21/25School of Cancer Sciences
315960CRUK Centre Renewal 2021Owen SansomCancer Research UK (CRUK)CTRQQR-2021\100006SCS - Beatson Institute for Cancer Research