Human-correlated genetic models identify precision therapy for liver cancer
成果类型：
Article
署名作者：
Muller, Miryam; May, Stephanie; Hall, Holly; Kendall, Timothy J.; Mcgarry, Lynn; Blukacz, Lauriane; Nuciforo, Sandro; Georgakopoulou, Anastasia; Jamieson, Thomas; Phinichkusolchit, Narisa; Dhayade, Sandeep; Suzuki, Toshiyasu; Huguet-Pradell, Julia; Powley, Ian R.; Officer-Jones, Leah; Pennie, Rachel L.; Esteban-Fabro, Roger; Gris-Oliver, Albert; Pinyol, Roser; Skalka, George L.; Leslie, Jack; Hoare, Matthew; Sprangers, Joep; Malviya, Gaurav; Mackintosh, Agata; Johnson, Emma; Mccain, Misti; Halpin, John; Kiourtis, Christos; Nixon, Colin; Clark, Graeme; Clark, William; Shaw, Robin; Hedley, Ann; Drake, Thomas M.; Tan, Ee Hong; Neilson, Matt; Murphy, Daniel J.; Lewis, David Y.; Reeves, Helen L.; Le Quesne, John; Mann, Derek A.; Carlin, Leo M.; Blyth, Karen; Llovet, Josep M.; Heim, Markus H.; Sansom, Owen J.; Miller, Crispin J.; Bird, Thomas G.
署名单位：
University of Glasgow; University of Edinburgh; University of Basel; University of Barcelona; Hospital Clinic de Barcelona; IDIBAPS; Newcastle University - UK; Newcastle University - UK; University of Cambridge; Cambridge University Hospitals NHS Foundation Trust; Addenbrooke's Hospital; University of Cambridge; University of Edinburgh; Newcastle University - UK; Newcastle Upon Tyne Hospitals NHS Foundation Trust; Queen Elizabeth University Hospital (QEUH); Koc University; Icahn School of Medicine at Mount Sinai; ICREA
刊物名称：
Nature
ISSN/ISSBN：
0028-2571
DOI：
10.1038/s41586-025-08585-z
发表日期：
2025-03-20
关键词：
hepatocellular-carcinoma
molecular classification
mice
expression
sorafenib
mutations
landscape
organoids
package
cells
摘要：
Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is a leading cause of cancer-related mortality worldwide1,2. HCC occurs typically from a background of chronic liver disease, caused by a spectrum of predisposing conditions. Tumour development is driven by the expansion of clones that accumulate progressive driver mutations3, with hepatocytes the most likely cell of origin2. However, the landscape of driver mutations in HCC is broadly independent of the underlying aetiologies4. Despite an increasing range of systemic treatment options for advanced HCC, outcomes remain heterogeneous and typically poor. Emerging data suggest that drug efficacies depend on disease aetiology and genetic alterations5,6. Exploring subtypes in preclinical models with human relevance will therefore be essential to advance precision medicine in HCC7. Here we generated a suite of genetically driven immunocompetent in vivo and matched in vitro HCC models. Our models represent multiple features of human HCC, including clonal origin, histopathological appearance and metastasis. We integrated transcriptomic data from the mouse models with human HCC data and identified four common human-mouse subtype clusters. The subtype clusters had distinct transcriptomic characteristics that aligned with the human histopathology. In a proof-of-principle analysis, we verified response to standard-of-care treatment and used a linked in vitro-in vivo pipeline to identify a promising therapeutic candidate, cladribine, that has not previously been linked to HCC treatment. Cladribine acts in a highly effective subtype-specific manner in combination with standard-of-care therapy.