Human-correlated genetic models identify precision therapy for liver cancer
Abstract
Abstract Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is a leading cause of cancer-related mortality worldwide 1,2 . 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 mutations 3 , with hepatocytes the most likely cell of origin 2 . However, the landscape of driver mutations in HCC is broadly independent of the underlying aetiologies 4 . 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 alterations 5,6 . Exploring subtypes in preclinical models with human relevance will therefore be essential to advance precision medicine in HCC 7 . 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.
Article Details
Authors (49)
Miryam Müller
Stephanie May
Holly Hall
Timothy J. Kendall
Lynn McGarry
Lauriane Blukacz
Sandro Nuciforo
Anastasia Georgakopoulou
Thomas Jamieson
Narisa Phinichkusolchit
Sandeep Dhayade
Toshiyasu Suzuki
Júlia Huguet-Pradell
Ian R. Powley
Leah Officer-Jones
Rachel L. Pennie
Roger Esteban-Fabró
Albert Gris-Oliver
Roser Pinyol
George L. Skalka
Jack Leslie
Matthew Hoare
Joep Sprangers
Gaurav Malviya
Agata Mackintosh
Emma Johnson
Misti McCain
John Halpin
Christos Kiourtis
Colin Nixon
Graeme Clark
William Clark
Robin Shaw
Ann Hedley
Thomas M. Drake
Ee Hong Tan
Matt Neilson
Daniel J. Murphy
David Y. Lewis
Helen L. Reeves
John Le Quesne
Derek A. Mann
Leo M. Carlin
Karen Blyth
Josep M. Llovet
Markus H. Heim
Owen J. Sansom
Crispin J. Miller
Thomas G. Bird