Jake June-Koo Lee

Although EGFR inhibitors are highly effective for treating EGFR- mutant lung adenocarcinomas ( EGFR + LUADs), resistance inevitably emerges, with histologic transformation to small cell lung cancer (SCLC) representing a particularly aggressive mechanism. Our prospective trial enrolled patients with EGFR + LUAD at high risk of transformation ( TP53 / RB1 -deficient) and treated them with first-line osimertinib combined with platinum and etoposide. Despite the addition of SCLC-directed chemotherapy, nearly half of patients (5 of 11) underwent SCLC transformation, with median progression-free survival of 11 months and overall survival of 33 months. Genomic and single-cell transcriptomic profiling of patient samples revealed clinical and subclinical plasticity associated with TP53 / RB1 comutations, including histological transformation to SCLC, as well as mesenchymal and squamous histologies. These changes in plasticity were linked to progressive disruption of the RB pathway, leading to altered chromatin accessibility and induction of neuronal differentiation and epithelial-to-mesenchymal transition transcriptional programs, further intensified by osimertinib treatment. These findings provide insights into the role of plasticity in mediating drug tolerance.

Chromosomal rearrangements can be oncogenic driver events in cancers. In contrast to hematological malignancies where chromosomal rearrangements are often initiated by the activation-induced cytidine deaminase (AID) enzyme, the mechanisms that induce rearrangements in solid cancers remain largely unknown. Here, we tested the activity of each of the 7 members of the apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3; A3) family enzymes with genome-wide rearrangement assays. We discovered that A3 enzymes induced focal clusters of rearrangements (FCRs) and dispersed clusters of rearrangements (DCRs). While AID-induced FCRs were enriched near transcription start sites (TSS) and within gene bodies, A3-induced FCRs were mainly located within gene bodies with limited activity at the TSS. AID- and A3-induced rearrangements primarily occurred in early replication timing regions, A compartments, and topologically associated domain boundaries. A3A showed superior activity to induce chromosomal rearrangements and mutations near breakpoints compared to other A3 family members. Remarkably, A3s promoted the formation of oncogenic tyrosine kinase (TK) fusions in lung cancer models in vitro and in vivo . Thus, A3 enzymes induce chromosomal rearrangements by recurrent patterns and enhance the formation of oncogenic fusions in cancers.

Classification of thymic epithelial tumors into three subgroups using PCA, k-means clustering, and NMF, along with correlations between non-tumor cell proportions and T cell markers

Characteristics of 137 thymic epithelial tumors, including clinical data, genomic alterations, and transcriptional signatures

Differential expression of lipid metabolism genes between GTF2I-type and CN-type thymomas is shown through box plots and scatter plots, revealing consistent expression differences not biased by tumor cell fraction and indicating that these transcripts originate mainly from tumor cells

IRS4's high expression in certain thymoma types, its tissue distribution, cellular expression patterns, regulatory associations, prognostic significance, and the presence of a cryptic exon influencing IRS4 transcripts

Validation of thymic epithelial tumor subgroups using single-cell RNA-seq data, including UMAP projections, gene expression heatmaps, inferred copy-number alterations, and mapping onto the normal TECs

List of gene sets used in immune component analysis

List of datasets used in single-cell RNA-seq analysis

Correlation between IRS4 expression levels and pathway scores using Pearson, Spearman, and linear regression with tumor cell fraction