FGFR3-TACC3 is an oncogenic fusion protein in respiratory epithelium

Sarah A. Best, Cassandra R. Harapas, Ariena Kersbergen, Vivek Rathi, Marie-Liesse Labat, Kate D. Sutherland

Research output: Contribution to journalArticle

Abstract

Structural rearrangements of the genome can drive lung tumorigenesis through the generation of fusion genes with oncogenic properties. Advanced genomic approaches have identified the presence of a genetic fusion between fibroblast growth factor receptor 3 (FGFR3) and transforming acidic coiled-coil 3 (TACC3) in non-small cell lung cancer (NSCLC), providing a novel target for FGFR inhibition. To interrogate the functional consequences of the FGFR3–TACC3 fusion in the transformation of lung epithelial cells, we generated a novel transgenic mouse model that expresses FGFR3–TACC3 concomitant with loss of the p53 tumor suppressor gene. Intranasal delivery of an Ad5-CMV-Cre virus promoted seromucinous glandular transformation of olfactory cells lining the nasal cavities of FGFR3–TACC3 (LSL–F3T3) mice, which was further accelerated upon loss of p53 (LSL–F3T3/p53). Surprisingly, lung tumors failed to develop in intranasally infected LSL–F3T3 and LSL–F3T3/p53 mice. In line with these observations, we demonstrated that intranasal delivery of Ad5-CMV-Cre induces widespread Cre-mediated recombination in the olfactory epithelium. Intra-tracheal delivery of Ad5-CMV-Cre into the lungs of LSL–F3T3 and LSL–F3T3/p53 mice, however, resulted in the development of lung adenocarcinomas. Taken together, these findings provide in vivo evidence for an oncogenic function of FGFR3–TACC3 in respiratory epithelium.

Original languageEnglish (US)
Pages (from-to)6096-6104
Number of pages9
JournalOncogene
Volume37
Issue number46
DOIs
StatePublished - Nov 15 2018
Externally publishedYes

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Receptor, Fibroblast Growth Factor, Type 3
Respiratory Mucosa
Nasal Cavity
Lung
Proteins
Olfactory Mucosa
Gene Fusion
Tumor Suppressor Genes
Non-Small Cell Lung Carcinoma
Transgenic Mice
Genetic Recombination
Carcinogenesis
Epithelial Cells
Genome
Viruses

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Best, S. A., Harapas, C. R., Kersbergen, A., Rathi, V., Labat, M-L., & Sutherland, K. D. (2018). FGFR3-TACC3 is an oncogenic fusion protein in respiratory epithelium. Oncogene, 37(46), 6096-6104. https://doi.org/10.1038/s41388-018-0399-5

FGFR3-TACC3 is an oncogenic fusion protein in respiratory epithelium. / Best, Sarah A.; Harapas, Cassandra R.; Kersbergen, Ariena; Rathi, Vivek; Labat, Marie-Liesse; Sutherland, Kate D.

In: Oncogene, Vol. 37, No. 46, 15.11.2018, p. 6096-6104.

Research output: Contribution to journalArticle

Best, SA, Harapas, CR, Kersbergen, A, Rathi, V, Labat, M-L & Sutherland, KD 2018, 'FGFR3-TACC3 is an oncogenic fusion protein in respiratory epithelium', Oncogene, vol. 37, no. 46, pp. 6096-6104. https://doi.org/10.1038/s41388-018-0399-5
Best SA, Harapas CR, Kersbergen A, Rathi V, Labat M-L, Sutherland KD. FGFR3-TACC3 is an oncogenic fusion protein in respiratory epithelium. Oncogene. 2018 Nov 15;37(46):6096-6104. https://doi.org/10.1038/s41388-018-0399-5
Best, Sarah A. ; Harapas, Cassandra R. ; Kersbergen, Ariena ; Rathi, Vivek ; Labat, Marie-Liesse ; Sutherland, Kate D. / FGFR3-TACC3 is an oncogenic fusion protein in respiratory epithelium. In: Oncogene. 2018 ; Vol. 37, No. 46. pp. 6096-6104.
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