MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer

Catherine M. Shachaf, Andrew M. Kopelman, Constadlna Arvanitis, Åsa Karlsson, Shelly Beer, Stefanie Mandl, Michael H. Bachmann, Alexander D Borowsky, Boris Ruebner, Robert Cardiff, Qiwei Yang, J. Michael Bishop, Christopher H. Contag, Dean W. Felsher

Research output: Contribution to journalArticle

573 Citations (Scopus)

Abstract

Hepatocellular carcinoma is generally refractory to clinical treatment. Here, we report that inactivation of the MYC oncogene is sufficient to induce sustained regression of invasive liver cancers. MYC inactivation resulted en masse in tumour cells differentiating into hepatocytes and biliary cells forming bile duct structures, and this was associated with rapid loss of expression of the tumour marker α-fetoprotein, the increase in expression of liver cell markers cytokeratin 8 and carcinoembryonic antigen, and in some cells the liver stem cell marker cytokeratin 19. Using in vivo bioluminescence imaging we found that many of these tumour cells remained dormant as long as MYC remain inactivated; however, MYC reactivation immediately restored their neoplastic features. Using array comparative genomic hybridization we confirmed that these dormant liver cells and the restored tumour retained the identical molecular signature and hence were clonally derived from the tumour cells. Our results show how oncogene inactivation may reverse tumorigenesis in the most clinically difficult cancers. Oncogene inactivation uncovers the pluripotent capacity of tumours to differentiate into normal cellular lineages and tissue structures, while retaining their latent potential to become cancerous, and hence existing in a state of tumour dormancy.

Original languageEnglish (US)
Pages (from-to)1112-1117
Number of pages6
JournalNature
Volume431
Issue number7012
DOIs
StatePublished - Oct 28 2004

Fingerprint

Liver Neoplasms
Oncogenes
Neoplasms
Liver
Fetal Proteins
Keratin-8
Keratin-19
Comparative Genomic Hybridization
Carcinoembryonic Antigen
Tumor Biomarkers
Bile Ducts
Hepatocytes
Hepatocellular Carcinoma
Carcinogenesis
Stem Cells

ASJC Scopus subject areas

  • General

Cite this

Shachaf, C. M., Kopelman, A. M., Arvanitis, C., Karlsson, Å., Beer, S., Mandl, S., ... Felsher, D. W. (2004). MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature, 431(7012), 1112-1117. https://doi.org/10.1038/nature03043

MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. / Shachaf, Catherine M.; Kopelman, Andrew M.; Arvanitis, Constadlna; Karlsson, Åsa; Beer, Shelly; Mandl, Stefanie; Bachmann, Michael H.; Borowsky, Alexander D; Ruebner, Boris; Cardiff, Robert; Yang, Qiwei; Bishop, J. Michael; Contag, Christopher H.; Felsher, Dean W.

In: Nature, Vol. 431, No. 7012, 28.10.2004, p. 1112-1117.

Research output: Contribution to journalArticle

Shachaf, CM, Kopelman, AM, Arvanitis, C, Karlsson, Å, Beer, S, Mandl, S, Bachmann, MH, Borowsky, AD, Ruebner, B, Cardiff, R, Yang, Q, Bishop, JM, Contag, CH & Felsher, DW 2004, 'MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer', Nature, vol. 431, no. 7012, pp. 1112-1117. https://doi.org/10.1038/nature03043
Shachaf CM, Kopelman AM, Arvanitis C, Karlsson Å, Beer S, Mandl S et al. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature. 2004 Oct 28;431(7012):1112-1117. https://doi.org/10.1038/nature03043
Shachaf, Catherine M. ; Kopelman, Andrew M. ; Arvanitis, Constadlna ; Karlsson, Åsa ; Beer, Shelly ; Mandl, Stefanie ; Bachmann, Michael H. ; Borowsky, Alexander D ; Ruebner, Boris ; Cardiff, Robert ; Yang, Qiwei ; Bishop, J. Michael ; Contag, Christopher H. ; Felsher, Dean W. / MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. In: Nature. 2004 ; Vol. 431, No. 7012. pp. 1112-1117.
@article{08f3be75821a4ad2b6bf7c463f744419,
title = "MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer",
abstract = "Hepatocellular carcinoma is generally refractory to clinical treatment. Here, we report that inactivation of the MYC oncogene is sufficient to induce sustained regression of invasive liver cancers. MYC inactivation resulted en masse in tumour cells differentiating into hepatocytes and biliary cells forming bile duct structures, and this was associated with rapid loss of expression of the tumour marker α-fetoprotein, the increase in expression of liver cell markers cytokeratin 8 and carcinoembryonic antigen, and in some cells the liver stem cell marker cytokeratin 19. Using in vivo bioluminescence imaging we found that many of these tumour cells remained dormant as long as MYC remain inactivated; however, MYC reactivation immediately restored their neoplastic features. Using array comparative genomic hybridization we confirmed that these dormant liver cells and the restored tumour retained the identical molecular signature and hence were clonally derived from the tumour cells. Our results show how oncogene inactivation may reverse tumorigenesis in the most clinically difficult cancers. Oncogene inactivation uncovers the pluripotent capacity of tumours to differentiate into normal cellular lineages and tissue structures, while retaining their latent potential to become cancerous, and hence existing in a state of tumour dormancy.",
author = "Shachaf, {Catherine M.} and Kopelman, {Andrew M.} and Constadlna Arvanitis and {\AA}sa Karlsson and Shelly Beer and Stefanie Mandl and Bachmann, {Michael H.} and Borowsky, {Alexander D} and Boris Ruebner and Robert Cardiff and Qiwei Yang and Bishop, {J. Michael} and Contag, {Christopher H.} and Felsher, {Dean W.}",
year = "2004",
month = "10",
day = "28",
doi = "10.1038/nature03043",
language = "English (US)",
volume = "431",
pages = "1112--1117",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7012",

}

TY - JOUR

T1 - MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer

AU - Shachaf, Catherine M.

AU - Kopelman, Andrew M.

AU - Arvanitis, Constadlna

AU - Karlsson, Åsa

AU - Beer, Shelly

AU - Mandl, Stefanie

AU - Bachmann, Michael H.

AU - Borowsky, Alexander D

AU - Ruebner, Boris

AU - Cardiff, Robert

AU - Yang, Qiwei

AU - Bishop, J. Michael

AU - Contag, Christopher H.

AU - Felsher, Dean W.

PY - 2004/10/28

Y1 - 2004/10/28

N2 - Hepatocellular carcinoma is generally refractory to clinical treatment. Here, we report that inactivation of the MYC oncogene is sufficient to induce sustained regression of invasive liver cancers. MYC inactivation resulted en masse in tumour cells differentiating into hepatocytes and biliary cells forming bile duct structures, and this was associated with rapid loss of expression of the tumour marker α-fetoprotein, the increase in expression of liver cell markers cytokeratin 8 and carcinoembryonic antigen, and in some cells the liver stem cell marker cytokeratin 19. Using in vivo bioluminescence imaging we found that many of these tumour cells remained dormant as long as MYC remain inactivated; however, MYC reactivation immediately restored their neoplastic features. Using array comparative genomic hybridization we confirmed that these dormant liver cells and the restored tumour retained the identical molecular signature and hence were clonally derived from the tumour cells. Our results show how oncogene inactivation may reverse tumorigenesis in the most clinically difficult cancers. Oncogene inactivation uncovers the pluripotent capacity of tumours to differentiate into normal cellular lineages and tissue structures, while retaining their latent potential to become cancerous, and hence existing in a state of tumour dormancy.

AB - Hepatocellular carcinoma is generally refractory to clinical treatment. Here, we report that inactivation of the MYC oncogene is sufficient to induce sustained regression of invasive liver cancers. MYC inactivation resulted en masse in tumour cells differentiating into hepatocytes and biliary cells forming bile duct structures, and this was associated with rapid loss of expression of the tumour marker α-fetoprotein, the increase in expression of liver cell markers cytokeratin 8 and carcinoembryonic antigen, and in some cells the liver stem cell marker cytokeratin 19. Using in vivo bioluminescence imaging we found that many of these tumour cells remained dormant as long as MYC remain inactivated; however, MYC reactivation immediately restored their neoplastic features. Using array comparative genomic hybridization we confirmed that these dormant liver cells and the restored tumour retained the identical molecular signature and hence were clonally derived from the tumour cells. Our results show how oncogene inactivation may reverse tumorigenesis in the most clinically difficult cancers. Oncogene inactivation uncovers the pluripotent capacity of tumours to differentiate into normal cellular lineages and tissue structures, while retaining their latent potential to become cancerous, and hence existing in a state of tumour dormancy.

UR - http://www.scopus.com/inward/record.url?scp=7744220635&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=7744220635&partnerID=8YFLogxK

U2 - 10.1038/nature03043

DO - 10.1038/nature03043

M3 - Article

C2 - 15475948

AN - SCOPUS:7744220635

VL - 431

SP - 1112

EP - 1117

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7012

ER -