During library preparation, RNA from each nucleus receives an identifying barcode before complementary DNA is generated and sequenced. Computational analysis then uses those labels to associate sequence-derived expression measurements with their source nuclei rather than combining signals across the entire specimen. This preserves cell-to-cell variation, which is essential for examining heterogeneous tumors.
Some complex tissues and tumors do not readily yield intact, separable cells during sample preparation. Isolating nuclei provides an alternative material for transcriptomic analysis, allowing researchers to examine gene-expression patterns despite those dissociation challenges. The approach is also compatible with archived or frozen specimens, expanding studies beyond freshly collected tissue.
The resulting expression profiles can be compared across individual nuclei to identify distinct cellular populations within a tumor. This supports separation of malignant cells from surrounding stromal and immune populations based on their gene-expression patterns. Such resolution helps researchers describe tumor composition and examine how different populations contribute to the surrounding microenvironment.
Single-nucleus expression data can reveal gene-expression programs associated with tumor progression or treatment response. Researchers can examine whether particular cellular populations show patterns linked to advancing disease or changing therapeutic sensitivity. Because measurements remain resolved across nuclei, these programs can be connected to specific malignant, stromal, or immune components rather than treated as properties of the tumor as a whole.
A typical workflow begins by isolating nuclei from the specimen, followed by capture and barcoding of nuclear RNA. The labeled RNA is converted into complementary DNA, and the resulting libraries are sequenced. Computational analysis then interprets the sequence data as gene-expression profiles across nuclei, providing the basis for identifying cellular populations and expression programs.
It is particularly useful when investigators need to characterize complex tumors, analyze material that is difficult to dissociate, or work with archived and frozen specimens. Applications include molecular classification, assessment of tumor heterogeneity, characterization of tumor microenvironments, and investigation of expression programs associated with tumor progression or treatment response.