Molecular portraits of patients with intrahepatic cholangiocarcinoma who diverge as rapid progressors or long survivors on chemotherapy
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Molecular portraits of patients with intrahepatic cholangiocarcinoma who diverge as rapid progressors or long survivors on chemotherapy. / O'Rourke, Colm J.; Salati, Massimiliano; Rae, Colin; Carpino, Guido; Leslie, Holly; Pea, Antonio; Prete, Maria G.; Bonetti, Luca R.; Amato, Francesco; Montal, Robert; Upstill-Goddard, Rosie; Nixon, Colin; Sanchon-Sanchez, Paula; Kunderfranco, Paolo; Sia, Daniela; Gaudio, Eugenio; Overi, Diletta; Cascinu, Stefano; Hogdall, Dan; Pugh, Sian; Domingo, Enric; Primrose, John N.; Bridgewater, John; Spallanzani, Andrea; Gelsomino, Fabio; Llovet, Josep M.; Calvisi, Diego F.; Boulter, Luke; Caputo, Francesco; Lleo, Ana; Jamieson, Nigel B.; Luppi, Gabriele; Dominici, Massimo; Andersen, Jesper B.; Braconi, Chiara.
In: Gut, Vol. 73, 2024, p. 496-508.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Molecular portraits of patients with intrahepatic cholangiocarcinoma who diverge as rapid progressors or long survivors on chemotherapy
AU - O'Rourke, Colm J.
AU - Salati, Massimiliano
AU - Rae, Colin
AU - Carpino, Guido
AU - Leslie, Holly
AU - Pea, Antonio
AU - Prete, Maria G.
AU - Bonetti, Luca R.
AU - Amato, Francesco
AU - Montal, Robert
AU - Upstill-Goddard, Rosie
AU - Nixon, Colin
AU - Sanchon-Sanchez, Paula
AU - Kunderfranco, Paolo
AU - Sia, Daniela
AU - Gaudio, Eugenio
AU - Overi, Diletta
AU - Cascinu, Stefano
AU - Hogdall, Dan
AU - Pugh, Sian
AU - Domingo, Enric
AU - Primrose, John N.
AU - Bridgewater, John
AU - Spallanzani, Andrea
AU - Gelsomino, Fabio
AU - Llovet, Josep M.
AU - Calvisi, Diego F.
AU - Boulter, Luke
AU - Caputo, Francesco
AU - Lleo, Ana
AU - Jamieson, Nigel B.
AU - Luppi, Gabriele
AU - Dominici, Massimo
AU - Andersen, Jesper B.
AU - Braconi, Chiara
N1 - Publisher Copyright: © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - chemotherapy
KW - cholangiocarcinoma
KW - liver
U2 - 10.1136/gutjnl-2023-330748
DO - 10.1136/gutjnl-2023-330748
M3 - Journal article
C2 - 37758326
AN - SCOPUS:85172998768
VL - 73
SP - 496
EP - 508
JO - Gut
JF - Gut
SN - 0017-5749
ER -
ID: 369924338