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 language | English (US) |
|---|---|
| Pages (from-to) | 6096-6104 |
| Number of pages | 9 |
| Journal | Oncogene |
| Volume | 37 |
| Issue number | 46 |
| DOIs | |
| State | Published - Nov 15 2018 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research
Cite this
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 journal › Article
}
TY - JOUR
T1 - FGFR3-TACC3 is an oncogenic fusion protein in respiratory epithelium
AU - Best, Sarah A.
AU - Harapas, Cassandra R.
AU - Kersbergen, Ariena
AU - Rathi, Vivek
AU - Labat, Marie-Liesse
AU - Sutherland, Kate D.
PY - 2018/11/15
Y1 - 2018/11/15
N2 - 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.
AB - 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.
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U2 - 10.1038/s41388-018-0399-5
DO - 10.1038/s41388-018-0399-5
M3 - Article
VL - 37
SP - 6096
EP - 6104
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 46
ER -