Rb1 family mutation is sufficient for sarcoma initiation

Yongqing Liu, Ester Sánchez-Tilló, Xiaoqin Lu, Brian Clem, Sucheta Telang, Alfred B. Jenson, Miriam Cuatrecasas, Jason Chesney, Antonio Postigo () and Douglas C. Dean ()
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Yongqing Liu: Molecular Targets Program, James Brown Cancer Center, University of Louisville Health Sciences Center
Ester Sánchez-Tilló: Group of Transcriptional Regulation of Gene Expression, CIBERehd, IDIBAPS
Xiaoqin Lu: University of Louisville Health Sciences Center
Brian Clem: Molecular Targets Program, James Brown Cancer Center, University of Louisville Health Sciences Center
Sucheta Telang: Molecular Targets Program, James Brown Cancer Center, University of Louisville Health Sciences Center
Alfred B. Jenson: Molecular Targets Program, James Brown Cancer Center, University of Louisville Health Sciences Center
Miriam Cuatrecasas: Hospital Clinic
Jason Chesney: Molecular Targets Program, James Brown Cancer Center, University of Louisville Health Sciences Center
Antonio Postigo: Molecular Targets Program, James Brown Cancer Center, University of Louisville Health Sciences Center
Douglas C. Dean: Molecular Targets Program, James Brown Cancer Center, University of Louisville Health Sciences Center

Nature Communications, 2013, vol. 4, issue 1, 1-10

Abstract: Abstract It is thought that genomic instability precipitated by Rb1 pathway loss rapidly triggers additional cancer gene mutations, accounting for rapid tumour onset following Rb1 mutation. However, recent whole-genome sequencing of retinoblastomas demonstrated little genomic instability, but instead suggested rapid epigenetic activation of cancer genes. These results raise the possibility that loss of the Rb1 pathway, which is a hallmark of cancers, might be sufficient for cancer initiation. Yet, mutation of the Rb1 family or inactivation of the Rb1 pathway in primary cells has proven insufficient for tumour initiation. Here we demonstrate that traditional nude mouse assays impose an artificial anoikis and proliferation barrier that prevents Rb1 family mutant fibroblasts from initiating tumours. By circumventing this barrier, we show that primary fibroblasts with only an Rb1 family mutation efficiently form sarcomas in nude mice, and a Ras-ZEB1-Akt pathway then causes transition of these tumours to an invasive phenotype.

Date: 2013
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DOI: 10.1038/ncomms3650

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