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MYC and MET cooperatively drive hepatocellular carcinoma with distinct molecular traits and vulnerabilities
Enhanced activation of the transcription factor MYC and of the receptor tyrosine kinase MET are among the events frequently occurring in hepatocellular carcinoma (HCC). Both genes individually act as drivers of liver cancer initiation and progression. However, their concomitant alteration in HCC has...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9700715/ https://www.ncbi.nlm.nih.gov/pubmed/36433941 http://dx.doi.org/10.1038/s41419-022-05411-6 |
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author | Sequera, Celia Grattarola, Margherita Holczbauer, Agnes Dono, Rosanna Pizzimenti, Stefania Barrera, Giuseppina Wangensteen, Kirk J. Maina, Flavio |
author_facet | Sequera, Celia Grattarola, Margherita Holczbauer, Agnes Dono, Rosanna Pizzimenti, Stefania Barrera, Giuseppina Wangensteen, Kirk J. Maina, Flavio |
author_sort | Sequera, Celia |
collection | PubMed |
description | Enhanced activation of the transcription factor MYC and of the receptor tyrosine kinase MET are among the events frequently occurring in hepatocellular carcinoma (HCC). Both genes individually act as drivers of liver cancer initiation and progression. However, their concomitant alteration in HCC has not been explored, nor functionally documented. Here, we analysed databases of five independent human HCC cohorts and found a subset of patients with high levels of MYC and MET (MYC(high)/MET(high)) characterised by poor prognosis. This clinical observation drove us to explore the functionality of MYC and MET co-occurrence in vivo, combining hydrodynamic tail vein injection for MYC expression in the R26(stopMet) genetic setting, in which wild-type MET levels are enhanced following the genetic deletion of a stop cassette. Results showed that increased MYC and MET expression in hepatocytes is sufficient to induce liver tumorigenesis even in the absence of pre-existing injuries associated with a chronic disease state. Intriguingly, ectopic MYC in MET tumours increases expression of the Mki67 proliferation marker, and switches them into loss of Afp, Spp1, Gpc3, Epcam accompanied by an increase in Hgma1, Vim, and Hep-Par1 levels. We additionally found a switch in the expression of specific immune checkpoints, with an increase in the Ctla-4 and Lag3 lymphocyte co-inhibitory responses, and in the Icosl co-stimulatory responses of tumour cells. We provide in vitro evidence on the vulnerability of some human HCC cell lines to combined MYC and MET targeting, which are otherwise resistant to single inhibition. Mechanistically, combined blockage of MYC and MET converts a partial cytostatic effect, triggered by individual blockage of MYC or MET, into a cytotoxic effect. Together, these findings highlight a subgroup of HCC characterised by MYC(high)/MET(high), and document functional cooperativity between MYC and MET in liver tumorigenesis. Thus, the MYC-R26(Met) model is a relevant setting for HCC biology, patient classification and treatment. |
format | Online Article Text |
id | pubmed-9700715 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-97007152022-11-27 MYC and MET cooperatively drive hepatocellular carcinoma with distinct molecular traits and vulnerabilities Sequera, Celia Grattarola, Margherita Holczbauer, Agnes Dono, Rosanna Pizzimenti, Stefania Barrera, Giuseppina Wangensteen, Kirk J. Maina, Flavio Cell Death Dis Article Enhanced activation of the transcription factor MYC and of the receptor tyrosine kinase MET are among the events frequently occurring in hepatocellular carcinoma (HCC). Both genes individually act as drivers of liver cancer initiation and progression. However, their concomitant alteration in HCC has not been explored, nor functionally documented. Here, we analysed databases of five independent human HCC cohorts and found a subset of patients with high levels of MYC and MET (MYC(high)/MET(high)) characterised by poor prognosis. This clinical observation drove us to explore the functionality of MYC and MET co-occurrence in vivo, combining hydrodynamic tail vein injection for MYC expression in the R26(stopMet) genetic setting, in which wild-type MET levels are enhanced following the genetic deletion of a stop cassette. Results showed that increased MYC and MET expression in hepatocytes is sufficient to induce liver tumorigenesis even in the absence of pre-existing injuries associated with a chronic disease state. Intriguingly, ectopic MYC in MET tumours increases expression of the Mki67 proliferation marker, and switches them into loss of Afp, Spp1, Gpc3, Epcam accompanied by an increase in Hgma1, Vim, and Hep-Par1 levels. We additionally found a switch in the expression of specific immune checkpoints, with an increase in the Ctla-4 and Lag3 lymphocyte co-inhibitory responses, and in the Icosl co-stimulatory responses of tumour cells. We provide in vitro evidence on the vulnerability of some human HCC cell lines to combined MYC and MET targeting, which are otherwise resistant to single inhibition. Mechanistically, combined blockage of MYC and MET converts a partial cytostatic effect, triggered by individual blockage of MYC or MET, into a cytotoxic effect. Together, these findings highlight a subgroup of HCC characterised by MYC(high)/MET(high), and document functional cooperativity between MYC and MET in liver tumorigenesis. Thus, the MYC-R26(Met) model is a relevant setting for HCC biology, patient classification and treatment. Nature Publishing Group UK 2022-11-24 /pmc/articles/PMC9700715/ /pubmed/36433941 http://dx.doi.org/10.1038/s41419-022-05411-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Sequera, Celia Grattarola, Margherita Holczbauer, Agnes Dono, Rosanna Pizzimenti, Stefania Barrera, Giuseppina Wangensteen, Kirk J. Maina, Flavio MYC and MET cooperatively drive hepatocellular carcinoma with distinct molecular traits and vulnerabilities |
title | MYC and MET cooperatively drive hepatocellular carcinoma with distinct molecular traits and vulnerabilities |
title_full | MYC and MET cooperatively drive hepatocellular carcinoma with distinct molecular traits and vulnerabilities |
title_fullStr | MYC and MET cooperatively drive hepatocellular carcinoma with distinct molecular traits and vulnerabilities |
title_full_unstemmed | MYC and MET cooperatively drive hepatocellular carcinoma with distinct molecular traits and vulnerabilities |
title_short | MYC and MET cooperatively drive hepatocellular carcinoma with distinct molecular traits and vulnerabilities |
title_sort | myc and met cooperatively drive hepatocellular carcinoma with distinct molecular traits and vulnerabilities |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9700715/ https://www.ncbi.nlm.nih.gov/pubmed/36433941 http://dx.doi.org/10.1038/s41419-022-05411-6 |
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