Müller, M. et al. (2022) Human-correlated genetic HCC models identify combination therapy for precision medicine [Pre-print]. Research Square, (doi: 10.21203/rs.3.rs-1638504/v1)
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Abstract
Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is a leading cause of cancer related mortality worldwide. 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 accumulated progressive driver mutations, with hepatocytes the most likely cell of origin. However, the landscape of driver mutations in HCC is independent of the underlying aetiologies. 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. Exploring subtypes in preclinical models with human relevance will therefore be essential to advance precision medicine in HCC. We generated over twenty-five new genetically-driven in vivo and in vitro HCC models. Our models represent multiple features of human HCC, including clonal origin, histopathological appearance, and metastasis to distant organs. 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 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 been linked to HCC treatment before. Cladribine acts in a highly effective subtype-specific manner in combination with standard of care therapy.
| Item Type: | Articles |
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| Additional Information: | M.Mü. and T.G.B. were funded by the Wellcome Trust (Grant number: WT107492Z) and T.G.B and E.H.T. by the CRUK HUNTER Accelerator Award (Grant number: 175 A26813). S.D, N.P., and K.B. were funded by CRUK (Grant numbers A29799, A17196, and A31287). H.L.R and M.Mc were funded by CRUK centre grant (C9380/A18084), programme grant (C18342/A23390) and Accelerator award (C9380/A26813). C.K was funded by CRUK (Grant number A17196 and A31287). D.L. was funded by Cancer Research UK (Grant number: A25006). L.M.C was funded by Cancer Research UK (Grant number: A23983). O.J.S. was funded by Cancer Research UK (Grant number: A21139, A17196, and A31287). H.H. and C.M. were funded by Cancer Research UK (Grant number: A29801). |
| Status: | Published |
| Refereed: | No |
| Glasgow Author(s) Enlighten ID: | Blyth, Professor Karen and Murphy, Professor Daniel and Malviya, Dr Gaurav and Bird, Dr Thomas and Muller, Dr Miryam and Carlin, Dr Leo and Clark, Mr William and Miller, Professor Crispin and Lewis, Dr David and McGarry, Ms Lynn and Sansom, Professor Owen |
| Authors: | Müller, M., May, S., Hall, H., Kendall, T. J., McGarry, L., Blukacz, L., Nuciforo, S., Jamieson, T., Phinichkusolchit, N., Dhayade, S., Leslie, J., Sprangers, J., Malviya, G., Mrowinska, A., Johnson, E., McCain, M., Halpin, J., Kiourtis, C., Georgakopoulou, A., Nixon, C., Clark, W., Shaw, R., Hedley, A., Drake, T. M., Tan, E. H., Neilson, M., Murphy, D. J., Lewis, D., Reeves, H. L., Mann, D. A., Blyth, K., Heim, M. H., Carlin, L. M., Sansom, O. J., Miller, C., and Bird, T. G. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Research Square |
| Copyright Holders: | Copyright © 2022 The Authors |
| First Published: | First published in Research Square 2022 |
| Publisher Policy: | Reproduced under a Creative Commons license |
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