Biology subjects

Lee, J. J.-K.

Publications and source records attributed to Lee, J. J.-K..

3 recordsLinked to original sources

bioRxiv2026

Evolution of oncogene amplification across 86,000 cancer cell genomes

High-level copy-number (CN) amplification (HLAMP) is a major mechanism of oncogene activation in human cancer. Despite progress in therapeutically targeting amplified oncogenes, the processes underlying amplicon evolution remain incompletely understood, leaving critical knowledge gaps in their etiology and mechanisms of therapeutic response. To address this, we analyzed the evolutionary trajectories of HLAMPs using single-cell whole-genome sequencing data from 86,239 cancer cells across 93 patients and 9 experimental systems. We found that cell-to-cell CN variability provides a quantifiable readout of HLAMP mechanism, clearly distinguishing extrachromosomal circular DNA (ecDNA) from intrachromosomal amplification (ICamp) through characteristic CN distributions that reflect distinct modes of segregation and correspond to clonal architecture. Notably, ICamp events frequently showed multiple amplitude peaks specific to subclones, indicating punctuated shifts in oncogene dosage through numeric or structural modulatory mechanisms with transcriptional impact. In contrast, ecDNAs exhibited broad, continuous CN distribution with extreme high-copy outliers, consistent with asymmetric segregation. The CN and structural diversity of ecDNA regions enabled systematic deconvolution of ecDNA subspecies and estimation of their per-cell abundance, revealing the history of ecDNA-mediated oncogenesis at single-nucleotide resolution. We observed ecDNA diversification through internal rearrangements across cases and, notably, convergent evolution in glioblastoma cases marked by multiple, recurrent acquisition of EGFR-targeting ecDNAs. Finally, single-cell genome-based identification of ecDNAs showed substantial discrepancy with bulk genome graph-based predictions and reliably distinguished actively maintained ecDNAs from historical genomic footprints after chromosomal re-integration. These findings reveal marked tissue-type specificity of ecDNAs, suggesting that ecDNA-mediated oncogenesis may depend on a permissive tissue context.

genomics↗

bioRxiv2025

Complementary modes of resistance to EGFR TKI in lung adenocarcinoma through MAPK activation and cellular plasticity

EGFR-mutant lung adenocarcinoma (LUAD) represents 20% of all non-small cell lung carcinomas, with most patients presenting with incurable metastatic disease. Treatment with mutant-selective EGFR tyrosine kinase inhibitors (TKIs) results in initial tumor reduction, yet nearly all patients eventually relapse. The mechanisms driving drug resistance are incompletely understood, creating significant barriers to curing metastatic disease. We integrated clinical genomic and single-nuclei RNA (snRNA) sequencing from a cohort of 62 EGFR-mutant LUAD patients treated with the third generation EGFR TKI, osimertinib, and compared treatment-naive (TN), minimal residual disease (MRD), and progressive disease (PD) tumors. We found that disease progression is associated with a marked decrease in alveolar lineage fidelity, coincident with reduced MAPK signaling and adenocarcinoma identity. PD tumors with sustained MAPK pathway activity, such as those with EGFR or MET amplifications, tended to retain adenocarcinoma identity. In contrast, MAPK-low tumors were more likely to undergo histological transformation to squamous or neuroendocrine lineages. Remarkably, we observed rare tumor cell populations prior to treatment that were poorly differentiated, in some cases with neuroendocrine or squamous features. At progression, these histologically divergent tumor cells increased in prevalence, both in cases with overt histological transformation, and in others with sub-clinical histological plasticity. These findings suggest that pre-existing capacity for histologic plasticity may be a substrate for therapy induced selection. Taken together, our results illuminate genomically encoded MAPK signaling and lineage plasticity as complementary mechanisms of acquired resistance to EGFR TKI in lung adenocarcinoma.

cancer biology↗

bioRxiv2021

APOBEC3A drives acquired resistance to targeted therapies in non-small cell lung cancer

Acquired drug resistance to even the most effective anti-cancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified1-6, the underlying molecular mechanisms shaping tumor evolution during treatment are incompletely understood. The extent to which therapy actively drives tumor evolution by promoting mutagenic processes7 or simply provides the selective pressure necessary for the outgrowth of drug-resistant clones8 remains an open question. Here, we report that lung cancer targeted therapies commonly used in the clinic induce the expression of cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Induction of A3A facilitated the formation of double-strand DNA breaks (DSBs) in cycling drug-treated cells, and fully resistant clones that evolved from drug-tolerant intermediates exhibited an elevated burden of chromosomal aberrations such as copy number alterations and structural variations. Preventing therapy-induced A3A mutagenesis either by gene deletion or RNAi-mediated suppression delayed the emergence of drug resistance. Finally, we observed accumulation of A3A mutations in lung cancer patients who developed drug resistance after treatment with sequential targeted therapies. These data suggest that induction of A3A mutagenesis in response to targeted therapy treatment may facilitate the development of acquired resistance in non-small-cell lung cancer. Thus, suppressing expression or enzymatic activity of A3A may represent a potential therapeutic strategy to prevent or delay acquired resistance to lung cancer targeted therapy.

cancer biology↗