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Ras/MAPK signalling intensity defines subclonal fitness in a mouse model of hepatocellular carcinoma

Quantitative differences in signal transduction are to date an understudied feature of tumour heterogeneity. The MAPK Erk pathway, which is activated in a large proportion of human tumours, is a prototypic example of distinct cell fates being driven by signal intensity. We have used primary hepatocy...

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Autores principales: Lozano, Anthony, Souche, Francois-Régis, Chavey, Carine, Dardalhon, Valérie, Ramirez, Christel, Vegna, Serena, Desandre, Guillaume, Riviere, Anaïs, Zine El Aabidine, Amal, Fort, Philippe, Akkari, Leila, Hibner, Urszula, Grégoire, Damien
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9891719/
https://www.ncbi.nlm.nih.gov/pubmed/36656749
http://dx.doi.org/10.7554/eLife.76294
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author Lozano, Anthony
Souche, Francois-Régis
Chavey, Carine
Dardalhon, Valérie
Ramirez, Christel
Vegna, Serena
Desandre, Guillaume
Riviere, Anaïs
Zine El Aabidine, Amal
Fort, Philippe
Akkari, Leila
Hibner, Urszula
Grégoire, Damien
author_facet Lozano, Anthony
Souche, Francois-Régis
Chavey, Carine
Dardalhon, Valérie
Ramirez, Christel
Vegna, Serena
Desandre, Guillaume
Riviere, Anaïs
Zine El Aabidine, Amal
Fort, Philippe
Akkari, Leila
Hibner, Urszula
Grégoire, Damien
author_sort Lozano, Anthony
collection PubMed
description Quantitative differences in signal transduction are to date an understudied feature of tumour heterogeneity. The MAPK Erk pathway, which is activated in a large proportion of human tumours, is a prototypic example of distinct cell fates being driven by signal intensity. We have used primary hepatocyte precursors transformed with different dosages of an oncogenic form of Ras to model subclonal variations in MAPK signalling. Orthotopic allografts of Ras-transformed cells in immunocompromised mice gave rise to fast-growing aggressive tumours, both at the primary location and in the peritoneal cavity. Fluorescent labelling of cells expressing different oncogene levels, and consequently varying levels of MAPK Erk activation, highlighted the selection processes operating at the two sites of tumour growth. Indeed, significantly higher Ras expression was observed in primary as compared to secondary, metastatic sites, despite the apparent evolutionary trade-off of increased apoptotic death in the liver that correlated with high Ras dosage. Analysis of the immune tumour microenvironment at the two locations suggests that fast peritoneal tumour growth in the immunocompromised setting is abrogated in immunocompetent animals due to efficient antigen presentation by peritoneal dendritic cells. Furthermore, our data indicate that, in contrast to the metastatic-like outgrowth, strong MAPK signalling is required in the primary liver tumours to resist elimination by NK (natural killer) cells. Overall, this study describes a quantitative aspect of tumour heterogeneity and points to a potential vulnerability of a subtype of hepatocellular carcinoma as a function of MAPK Erk signalling intensity.
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spelling pubmed-98917192023-02-02 Ras/MAPK signalling intensity defines subclonal fitness in a mouse model of hepatocellular carcinoma Lozano, Anthony Souche, Francois-Régis Chavey, Carine Dardalhon, Valérie Ramirez, Christel Vegna, Serena Desandre, Guillaume Riviere, Anaïs Zine El Aabidine, Amal Fort, Philippe Akkari, Leila Hibner, Urszula Grégoire, Damien eLife Cancer Biology Quantitative differences in signal transduction are to date an understudied feature of tumour heterogeneity. The MAPK Erk pathway, which is activated in a large proportion of human tumours, is a prototypic example of distinct cell fates being driven by signal intensity. We have used primary hepatocyte precursors transformed with different dosages of an oncogenic form of Ras to model subclonal variations in MAPK signalling. Orthotopic allografts of Ras-transformed cells in immunocompromised mice gave rise to fast-growing aggressive tumours, both at the primary location and in the peritoneal cavity. Fluorescent labelling of cells expressing different oncogene levels, and consequently varying levels of MAPK Erk activation, highlighted the selection processes operating at the two sites of tumour growth. Indeed, significantly higher Ras expression was observed in primary as compared to secondary, metastatic sites, despite the apparent evolutionary trade-off of increased apoptotic death in the liver that correlated with high Ras dosage. Analysis of the immune tumour microenvironment at the two locations suggests that fast peritoneal tumour growth in the immunocompromised setting is abrogated in immunocompetent animals due to efficient antigen presentation by peritoneal dendritic cells. Furthermore, our data indicate that, in contrast to the metastatic-like outgrowth, strong MAPK signalling is required in the primary liver tumours to resist elimination by NK (natural killer) cells. Overall, this study describes a quantitative aspect of tumour heterogeneity and points to a potential vulnerability of a subtype of hepatocellular carcinoma as a function of MAPK Erk signalling intensity. eLife Sciences Publications, Ltd 2023-01-19 /pmc/articles/PMC9891719/ /pubmed/36656749 http://dx.doi.org/10.7554/eLife.76294 Text en © 2023, Lozano et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cancer Biology
Lozano, Anthony
Souche, Francois-Régis
Chavey, Carine
Dardalhon, Valérie
Ramirez, Christel
Vegna, Serena
Desandre, Guillaume
Riviere, Anaïs
Zine El Aabidine, Amal
Fort, Philippe
Akkari, Leila
Hibner, Urszula
Grégoire, Damien
Ras/MAPK signalling intensity defines subclonal fitness in a mouse model of hepatocellular carcinoma
title Ras/MAPK signalling intensity defines subclonal fitness in a mouse model of hepatocellular carcinoma
title_full Ras/MAPK signalling intensity defines subclonal fitness in a mouse model of hepatocellular carcinoma
title_fullStr Ras/MAPK signalling intensity defines subclonal fitness in a mouse model of hepatocellular carcinoma
title_full_unstemmed Ras/MAPK signalling intensity defines subclonal fitness in a mouse model of hepatocellular carcinoma
title_short Ras/MAPK signalling intensity defines subclonal fitness in a mouse model of hepatocellular carcinoma
title_sort ras/mapk signalling intensity defines subclonal fitness in a mouse model of hepatocellular carcinoma
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9891719/
https://www.ncbi.nlm.nih.gov/pubmed/36656749
http://dx.doi.org/10.7554/eLife.76294
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