scIRES-seq reveals multimodal molecular heterogeneity in CTCs from small cell cervical cancer

Circulating tumor cells (CTCs) offer insights into cancer dissemination mechanisms, yet their scarcity and heterogeneity pose challenges for accurate identification and molecular analysis. The research team devised scIRES-seq, a method that correlates immunophenotype, genetic differences, epigenomic markers, and gene expression within individual cells.

To validate its effectiveness, the researchers employed scIRES-seq alongside real-time imaging spectral flow cytometry on CTCs from a patient with metastatic cervical small cell neuroendocrine carcinoma. By comparing tumor-matched copy-number alterations and targeted somatic variants, they confirmed CTC identity, corroborated by DNA methylation profiles that mirrored the characteristics of metastatic tissue and transcriptional markers indicative of neuroendocrine differentiation.

Genetic and DNA methylation analyses revealed two predominantly congruent CTC subpopulations, which were not easily differentiated by their transcriptomes, underscoring the value of single-cell multi-omics profiling in providing complementary data. This study confirms the viability of integrated CTC identification and characterization, offering a framework for exploring the connections between genetic diversity and molecular states in infrequent and heterogeneous cell populations.