Abstract 3891: Integrative single-cell tracking of genome evolution and tumor cell plasticity in small cell lung cancer (SCLC)

Abstract SCLC is the deadliest type of lung cancer, which is mostly diagnosed at late stages and accounts for 15% of pulmonary tumors. Chemotherapy is initially effective, but SCLC patients relapse quickly and develop resistant tumors. Large-scale studies uncovered key molecular patterns in SCLC, which include universal loss of TP53 and RB1, as well as transcriptional patterns based on the expression of 4 lineage transcription factors (TF). We aimed to dissect how genomic cues impact transcriptional phenotypes, and the dynamics of tumor and immune cell interactions, to thus decipher molecular mechanisms of phenotypic divergence in SCLC. We performed genome and single cell transcriptome profiling on 56 SCLC patient tumors, including primary tumors, metastases and paired relapse tumors, including a patient sample after treatment with DLL3-targeted immunotherapy. Single cell RNA-seq was performed with the 10x Genomics platform to study cancer cells and the tumor micro-environment (TME), and tumor cell intrinsic heterogeneity. Data were processed with an in-house pipeline. Single cell expression profiles were determined for > 200000 cells from 56 tumors. Transcriptome profiling at single cell levels revealed co-expression of at least two of the lineage TF ASCL1, NEUROD1 or POU2F3 for each SCLC tumor. Transcriptional profiles pointed to a marked intra- and interpatient, as well as to inter-metastatic heterogeneity. Cell-cell-interaction analysis across all samples uncovered recurrent patterns of intra-tumoral receptor-ligand interactions. The integrative analysis of genome and single cell transcriptome data pointed to somatic alterations and copy number alterations shaping transcriptional heterogeneity. Specifically, tumors with gene amplifications of MYC family members share similar expression profiles. We performed multi-regional and longitudinal studies of matched patient cases to project genomic patterns of clonal evolution to transcriptional profiles at single cell level, thus analyzing the effect of genome diversity on the transcriptional landscape. Additionally, tumor intrinsic profiles of heterogeneity were mapped to single cell data of patient tumors to elucidate the effects on tumor-immune cell interactions. Altogether we provide a first comprehensive framework for the study of underlying genetic alterations that shape the transcriptional landscape and phenotypic plasticity in SCLC. Our data points to a concerted regulation of a multitude of factors including lineage TF, transcriptional programs and interaction networks in SCLC. Citation Format: Marcel Schmiel, Laura Kaiser, Julie George, Roman K. Thomas. Integrative single-cell tracking of genome evolution and tumor cell plasticity in small cell lung cancer (SCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3891.