The developmental transcription factor ELF3 is critical for lung tumourigenesis
Session type: Oral
Oncogenic reactivation of transcription factors involved in fetal lung development is integral to lung adenocarcinoma (LUAD) biology, as observed with TITF1/NKX2-1. The ETS transcription factor ELF3 is implicated in fetal lung development and is encoded at 1q32.1. Chromosome 1q is a region of frequent gain in LUAD that lacks a bona fide oncogene. We hypothesize that ELF3 is a novel oncogene in LUAD.
We performed a multi-omics analysis of ELF3 in 1,685 clinical samples of LUAD, lung squamous cell carcinoma, small cell lung cancer, and non-malignant lung tissues. Protein-protein interaction (PPI) networks were constructed around ELF3 and pathway analysis was performed to understand the signalling disruptions resulting from ELF3 overexpression. Isogenic cell lines were established to assess the ability of ELF3 to regulate oncogenic phenotypes. The effect of ELF3 loss on tumour growth was assessed in xenograft mouse models.
ELF3 overexpression was exclusively observed in LUAD (40-73%), and was associated with poor overall survival, even in Stage I patients (p<0.0001). While mutations in ELF3 were rare, up to 80% of LUAD patients harboured focal amplification, DNA gain, and/or promoter hypomethylation at the ELF3 locus. PPI analysis suggests normal ELF3 interactions with MYC and TGF-beta are disrupted in LUAD. ELF3 overexpression induces a drastic shift in PPI networks, forming new interactions with NKX2-1 and ERBB3. This reprogramming of PPI networks affects several oncogenic pathways including MAPK, TGF-beta and WNT. ELF3 knockdown resulted in significantly reduced proliferation, viability, and anchorage-independent growth. Loss of ELF3 abolished the ability of LUAD cells to establish tumours in xenograft mouse models, demonstrating the requirement of ELF3 expression for tumour growth.
We have established that ELF3 plays a key role in LUAD biology. Forced reduction in ELF3 expression unequivocally arrests tumour growth demonstrating its therapeutic promise for the 73% of patients with ELF3 overexpression.