Cooperation Between Distinct Cancer Driver Genes Underlies Intertumor Heterogeneity in Hepatocellular Carcinoma.
Animals
Carcinoma, Hepatocellular
/ genetics
Cell Line, Tumor
Computational Biology
Disease Models, Animal
Drug Resistance, Neoplasm
/ genetics
Female
Gene Expression Regulation, Neoplastic
/ immunology
Genetic Heterogeneity
Humans
Liver Neoplasms
/ immunology
Male
Mice
Mice, Transgenic
Proto-Oncogenes
/ genetics
Tumor Escape
/ genetics
Tumor Microenvironment
/ genetics
Cancer Driver Genes
Cooperation
Intertumor Heterogeneity
Mouse Models
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
19
06
2020
revised:
29
07
2020
accepted:
11
08
2020
pubmed:
20
8
2020
medline:
16
4
2021
entrez:
20
8
2020
Statut:
ppublish
Résumé
The pattern of genetic alterations in cancer driver genes in patients with hepatocellular carcinoma (HCC) is highly diverse, which partially explains the low efficacy of available therapies. In spite of this, the existing mouse models only recapitulate a small portion of HCC inter-tumor heterogeneity, limiting the understanding of the disease and the nomination of personalized therapies. Here, we aimed at establishing a novel collection of HCC mouse models that captured human HCC diversity. By performing hydrodynamic tail-vein injections, we tested the impact of altering a well-established HCC oncogene (either MYC or β-catenin) in combination with an additional alteration in one of eleven other genes frequently mutated in HCC. Of the 23 unique pairs of genetic alterations that we interrogated, 9 were able to induce HCC. The established HCC mouse models were characterized at histopathological, immune, and transcriptomic level to identify the unique features of each model. Murine HCC cell lines were generated from each tumor model, characterized transcriptionally, and used to identify specific therapies that were validated in vivo. Cooperation between pairs of driver genes produced HCCs with diverse histopathology, immune microenvironments, transcriptomes, and drug responses. Interestingly, MYC expression levels strongly influenced β-catenin activity, indicating that inter-tumor heterogeneity emerges not only from specific combinations of genetic alterations but also from the acquisition of expression-dependent phenotypes. This novel collection of murine HCC models and corresponding cell lines establishes the role of driver genes in diverse contexts and enables mechanistic and translational studies.
Sections du résumé
BACKGROUND AND AIMS
The pattern of genetic alterations in cancer driver genes in patients with hepatocellular carcinoma (HCC) is highly diverse, which partially explains the low efficacy of available therapies. In spite of this, the existing mouse models only recapitulate a small portion of HCC inter-tumor heterogeneity, limiting the understanding of the disease and the nomination of personalized therapies. Here, we aimed at establishing a novel collection of HCC mouse models that captured human HCC diversity.
METHODS
By performing hydrodynamic tail-vein injections, we tested the impact of altering a well-established HCC oncogene (either MYC or β-catenin) in combination with an additional alteration in one of eleven other genes frequently mutated in HCC. Of the 23 unique pairs of genetic alterations that we interrogated, 9 were able to induce HCC. The established HCC mouse models were characterized at histopathological, immune, and transcriptomic level to identify the unique features of each model. Murine HCC cell lines were generated from each tumor model, characterized transcriptionally, and used to identify specific therapies that were validated in vivo.
RESULTS
Cooperation between pairs of driver genes produced HCCs with diverse histopathology, immune microenvironments, transcriptomes, and drug responses. Interestingly, MYC expression levels strongly influenced β-catenin activity, indicating that inter-tumor heterogeneity emerges not only from specific combinations of genetic alterations but also from the acquisition of expression-dependent phenotypes.
CONCLUSIONS
This novel collection of murine HCC models and corresponding cell lines establishes the role of driver genes in diverse contexts and enables mechanistic and translational studies.
Identifiants
pubmed: 32814112
pii: S0016-5085(20)35054-X
doi: 10.1053/j.gastro.2020.08.015
pmc: PMC7726023
mid: NIHMS1622792
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
2203-2220.e14Subventions
Organisme : NCI NIH HHS
ID : P30 CA196521
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA251155
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA230636
Pays : United States
Informations de copyright
Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.
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