Lung Cancer Biology

Our research moves from genome discovery into the functional analysis of lung cancer genome alterations.

Areas of interest include aneuploidy, EGFR structure and function, structure and function of amplified genes such as NKX2-1, modulators of immunotherapies like Xrn1, and analysis of novel lung cancer genes including the splicing factor U2AF1 and the RNA modifier CMTR2.

For aneuploidy, we developed a recombination-directed approach to generate chromosome aneuploidy and used this method to remove one copy of the chromosome arm 3p in human lung epithelial cells (Taylor et al., 2018). Follow up analysis of aneuploidy has revealed fitness effects of aneuploidy in the cancer genome and a specific role for loss of chromosome 8p (Shih et al., 2023).

CRISPR-Cas9 screening identified Xrn1 as an essential gene in cancer cell lines requiring ADAR1 with high interferon-stimulated gene expression. Knockout of Xrn1 led to dnRNA sensor PKR activation, inducing cancer cell death, revealing a possible unique vulnerability to target cancer cells (Xou et al., 2024).

Homozygous knockout of CMTR2 in mice led to embryonic lethality through defects in yolk-sac vascularization. Characterization of this knockout through bulk-RNA sequencing revealed p53 pathway activation and a reduction in the production of proliferation markers. This provides important roles of CMTR2 in gene regulation (Yermalovich et al., 2024).

Dosage modulation of NKX2-1 provides insight on how amplification and dosage of the transcription factor modulates oncogene regulation. Depletion of NKX2-1 resulted in downregulation of alveolar differentiation genes responsible for development of LUAD. Conversely, overexpression through constitutive promoters altered chromatin accessibility and contributed to EGFR TKI persistence (Pulice, Meyerson, 2025).

Methods in prime editing have revealed that mutant G12S KRAS forms a cryptic U2AF1 binding site that results in exon 2 skipping. However, introduction of an additional U2AF1 mutation can restore exon 2 inclusion by disrupting this interaction. (Walter et al., 2025). 

Watch this space for more news on some of the lung cancer genes—coming soon!