Spatial and Temporal Analysis Characterizes Evolution of Metastatic Lung Cancer

Metastatic disease accounts for the majority of cancer deaths, with lung cancer bearing a disproportionate burden. However, the mechanisms by which tumors spread remain poorly understood, limiting our ability to prevent or treat disseminated disease. Integrating samples from the TRACERx lung cancer study with the PEACE research autopsy program, Hessey, Bunkum, Huebner, Haase, Grigoriadis, Naceur-Lombardelli, and colleagues used whole-exome sequencing to reconstruct tumor evolutionary histories from longitudinally collected primary and metastatic samples from 24 patients with non–small cell lung cancer (NSCLC). Genomic analysis revealed that metastases diverged substantially from their originating primary tumors and harbored 11-fold greater heterogeneity than detected in prior limited-sampling studies, underscoring how single-biopsy approaches underestimate metastatic complexity. Mutational processes also differed between primary and metastatic subclones: Smoking- and APOBEC-associated damage were prominent in primary tumors, while metastases were enriched for clock-like mutations and, in treated patients, platinum chemotherapy–induced mutagenesis. Although many driver mutations were shared across primary and metastatic sites, with KRAS being the most frequently mutated oncogene, most patients harbored additional drivers found exclusively in metastases. Whole-genome doubling occurred in nearly all patients and arose throughout tumor evolution, further diversifying both primary tumors and metastases. Migration analyses showed that multiple primary tumor subclones seed early metastatic lesions, which then amplify disease through metastasis-to-metastasis spread in a self-propagating cascade of expansion and diversification. Metastases detected earlier were larger, more genomically diverse, and more likely to seed new lesions, suggesting a window of opportunity in which treating existing metastases could interrupt this cycle. Spread was largely confined within anatomic sites, and chromosomal instability was a key feature of subclones capable of crossing these boundaries. Together, these findings reveal the genomic diversity underlying metastatic NSCLC and demonstrate how comprehensive longitudinal sampling can capture this evolutionary process and may inform strategies to limit metastatic progression.Hessey S, Bunkum A, Huebner A, Haase K, Grigoriadis K, Naceur-Lombardelli C, et al. Evolutionary characterization of lung cancer metastasis. Nature 2026 Apr 29 Epub ahead of print.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.