FGFR3-TACC3 is an oncogenic fusion protein in respiratory epithelium

Sarah A Best1,2, Cassandra R Harapas1, Ariena Kersbergen1

  • 1ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.

Oncogene
|July 12, 2018
PubMed

Insights

The fibroblast growth factor receptor 3-transforming acidic coiled-coil 3 (FGFR3-TACC3) fusion drives lung cancer. This study shows FGFR3-TACC3 causes lung adenocarcinoma in mice, but not nasal tumors.

Area of Science:

  • Oncology
  • Genomics
  • Molecular Biology

Background:

  • Genomic rearrangements, including fusion genes, are key drivers of lung tumorigenesis.
  • The FGFR3-TACC3 fusion gene has been identified in non-small cell lung cancer (NSCLC), presenting a potential therapeutic target for FGFR inhibitors.

Purpose of the Study:

  • To investigate the functional role of the FGFR3-TACC3 fusion in lung epithelial cell transformation.
  • To establish and utilize a novel transgenic mouse model to study the oncogenic effects of FGFR3-TACC3, in conjunction with p53 tumor suppressor gene loss.

Main Methods:

  • Generation of a transgenic mouse model expressing FGFR3-TACC3 (LSL-F3T3) and its combination with p53 loss (LSL-F3T3/p53).
  • Administration of Ad5-CMV-Cre virus via intranasal and intra-tracheal routes to induce gene recombination.
  • Histopathological analysis of nasal cavities and lungs to assess tumor development and cellular transformation.

Main Results:

  • Intranasal viral delivery induced glandular transformation in olfactory cells but not lung tumors in both LSL-F3T3 and LSL-F3T3/p53 mice.
  • Intra-tracheal viral delivery into the lungs of LSL-F3T3 and LSL-F3T3/p53 mice led to the development of lung adenocarcinomas.
  • Cre-mediated recombination was confirmed in the olfactory epithelium following intranasal delivery.

Conclusions:

  • The FGFR3-TACC3 fusion gene possesses oncogenic properties in respiratory epithelium.
  • The location of gene activation (nasal vs. lung) influences tumor development, with direct lung targeting being crucial for adenocarcinoma formation.
  • This study provides in vivo validation of FGFR3-TACC3 as an oncogene in lung cancer.

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