Tissue specificity of oncogenic BRAF targeted to lung and thyroid through a shared lineage factor
Elin Schoultz,
Shawn Liang,
Therese Carlsson,
Stefan Filges,
Anders Ståhlberg,
Henrik Fagman,
Clotilde Wiel,
Volkan Sayin,
Mikael Nilsson
Affiliations
Elin Schoultz
Sahlgrenska Center for Cancer Research, University of Gothenburg, Göteborg, Sweden; Department of Medical Chemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden
Shawn Liang
Sahlgrenska Center for Cancer Research, University of Gothenburg, Göteborg, Sweden; Department of Medical Chemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden
Therese Carlsson
Sahlgrenska Center for Cancer Research, University of Gothenburg, Göteborg, Sweden; Department of Medical Chemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden
Stefan Filges
Sahlgrenska Center for Cancer Research, University of Gothenburg, Göteborg, Sweden; Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden
Anders Ståhlberg
Sahlgrenska Center for Cancer Research, University of Gothenburg, Göteborg, Sweden; Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden; Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Genetics and Genomics, Göteborg, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Göteborg, Sweden
Henrik Fagman
Sahlgrenska Center for Cancer Research, University of Gothenburg, Göteborg, Sweden; Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden
Clotilde Wiel
Sahlgrenska Center for Cancer Research, University of Gothenburg, Göteborg, Sweden; Department of Surgery, Institute of Clinical Sciences, University of Gothenburg, Göteborg, Sweden
Volkan Sayin
Sahlgrenska Center for Cancer Research, University of Gothenburg, Göteborg, Sweden; Department of Surgery, Institute of Clinical Sciences, University of Gothenburg, Göteborg, Sweden
Mikael Nilsson
Sahlgrenska Center for Cancer Research, University of Gothenburg, Göteborg, Sweden; Department of Medical Chemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden; Corresponding author
Summary: Cells of origin in cancer determine tumor phenotypes, but whether lineage-defining transcription factors might influence tissue specificity of tumorigenesis among organs with similar developmental traits are unknown. We demonstrate here that tumor development and progression markedly differ in lung and thyroid targeted by Braf mutation in Nkx2.1CreERT2 mice heterozygous for Nkx2-1. In absence of tamoxifen, non-induced Nkx2.1CreERT2;BrafCA/+ mutants developed multiple full-blown lung adenocarcinomas with a latency of 1–3 months whereas thyroid tumors were rare and constrained, although minute BrafCA activation documented by variant allele sequencing was similar in both tissues. Induced oncogene activation accelerated neoplastic growth only in the lungs. By contrast, NKX2-1+ progenitor cells were equally responsive to constitutive expression of mutant Braf during lung and thyroid development. Both lung and thyroid cells transiently downregulated NKX2-1 in early tumor stages. These results indicate that BRAFV600E-induced tumorigenesis obey organ-specific traits that might be differentially modified by a shared lineage factor.
