@article{05cd8a4cd0344818b615e056803506a5,
title = "Single-nucleus RNA sequencing of pre-malignant liver reveals disease-associated hepatocyte state with HCC prognostic potential",
abstract = "Current approaches to staging chronic liver diseases have limited utility for predicting liver cancer risk. Here, we employed single-nucleus RNA sequencing (snRNA-seq) to characterize the cellular microenvironment of healthy and pre-malignant livers using two distinct mouse models. Downstream analyses unraveled a previously uncharacterized disease-associated hepatocyte (daHep) transcriptional state. These cells were absent in healthy livers but increasingly prevalent as chronic liver disease progressed. Copy number variation (CNV) analysis of microdissected tissue demonstrated that daHep-enriched regions are riddled with structural variants, suggesting these cells represent a pre-malignant intermediary. Integrated analysis of three recent human snRNA-seq datasets confirmed the presence of a similar phenotype in human chronic liver disease and further supported its enhanced mutational burden. Importantly, we show that high daHep levels precede carcinogenesis and predict a higher risk of hepatocellular carcinoma development. These findings may change the way chronic liver disease patients are staged, surveilled, and risk stratified.",
keywords = "cancer surveillance, chronic liver disease, daHep, disease-associated hepatocyte, HCC, hepatocellular carcinoma, pre-malignancy, prognostic biomarker, snRNA-seq",
author = "Rodrigo Carlessi and Elena Denisenko and Ebru Boslem and Julia K{\"o}hn-Gaone and Nathan Main and {Abu Bakar}, {N. Dianah B.} and Shirolkar, {Gayatri D.} and Matthew Jones and Beasley, {Aaron B.} and Daniel Poppe and Dwyer, {Benjamin J.} and Connie Jackaman and Tjiam, {M. Christian} and Ryan Lister and Michael Karin and Fallowfield, {Jonathan A.} and Kendall, {Timothy J.} and Forbes, {Stuart J.} and Gray, {Elin S.} and Olynyk, {John K.} and George Yeoh and Forrest, {Alistair R.R.} and Ramm, {Grant A.} and Febbraio, {Mark A.} and Tirnitz-Parker, {Janina E.E.}",
note = "Funding Information: This work was supported by NHMRC Project Grants APP1031330 and APP1087125 to J.E.E.T.-P. G.A.R. and J.K.O. and APP1160323 to J.E.E.T.-P. G.A.R. J.K.O. and S.J.F. Our study was also supported by a Collaborative Cancer Research Grant from the Cancer Research Trust “Enabling advanced single-cell cancer genomics in Western Australia,” an Enabling Grant from the Cancer Council of Western Australia, and a Gastroenterological Society of Australia (GESA) Project Grant. Genomic data were generated at the Australian Cancer Research Foundation Centre for Advanced Cancer Genomics. R.C. is the recipient of a Cancer Council WA postdoctoral research fellowship. M.A.F. is supported by an Australian National Health and Medical Research Council (NHMRC) Investigator Grant (APP1194141) and by NHMRC Project/Ideas Grants (APP1042465, APP1041760, and APP1156511 to M.A.F. and APP1122227 to M.A.F. and M.K.). A.R.R.F. is supported by an NHMRC fellowship, APP1154524. Computational resources were provided by the Pawsey Supercomputing Centre supported by the governments of Australia and Western Australia. The authors would like to thank Dr. Ankur Sharma (Curtin University and Harry Perkins Institute of Medical Research) for valuable feedback and insight on data analysis and interpretation. R.C. conceived the study, designed and performed experiments, analyzed and interpretated data, and wrote the manuscript with J.E.E.T.-P. and M.A.F. E.D. performed pre-processing of sequencing data, analyzed and interpretated data, and critically appraised the manuscript. E.B. J.K.-G. N.M. N.D.B.A.B. G.D.S. M.J. A.B.B. D.P. B.J.D. C.J. and M.C.T. performed experiments. G.Y. conceived and designed some experiments, provided resources, and critically appraised the manuscript. R.L. E.S.G. J.K.O. G.A.R. S.F. A.R.R.F. and M.A.F. provided resources and critically appraised the manuscript. E.D. and A.R.R.F. provided critical advice on computational analysis. J.E.E.T.-P conceived the study, designed experiments, interpreted data, and critically appraised and edited the final manuscript. M.A.F. is the founder and shareholder of Celesta Therapeutics. Funding Information: This work was supported by NHMRC Project Grants APP1031330 and APP1087125 to J.E.E.T.-P., G.A.R., and J.K.O. and APP1160323 to J.E.E.T.-P., G.A.R., J.K.O., and S.J.F. Our study was also supported by a Collaborative Cancer Research Grant from the Cancer Research Trust “Enabling advanced single-cell cancer genomics in Western Australia,” an Enabling Grant from the Cancer Council of Western Australia, and a Gastroenterological Society of Australia (GESA) Project Grant. Genomic data were generated at the Australian Cancer Research Foundation Centre for Advanced Cancer Genomics. R.C. is the recipient of a Cancer Council WA postdoctoral research fellowship. M.A.F. is supported by an Australian National Health and Medical Research Council ( NHMRC ) Investigator Grant ( APP1194141 ) and by NHMRC Project/Ideas Grants ( APP1042465 , APP1041760 , and APP1156511 to M.A.F. and APP1122227 to M.A.F. and M.K.). A.R.R.F. is supported by an NHMRC fellowship, APP1154524 . Computational resources were provided by the Pawsey Supercomputing Centre supported by the governments of Australia and Western Australia. The authors would like to thank Dr. Ankur Sharma (Curtin University and Harry Perkins Institute of Medical Research) for valuable feedback and insight on data analysis and interpretation. Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = may,
day = "10",
doi = "10.1016/j.xgen.2023.100301",
language = "English",
volume = "3",
journal = "Cell Genomics",
issn = "2666-979X",
publisher = "Cell Press",
number = "5",
}
