Multimodal single-cell and whole-genome sequencing of small, frozen clinical specimens

Yiping Wang, Joy Linyue Fan, Johannes C. Melms, Amit Dipak Amin, Yohanna Georgis, Irving Barrera, Patricia Ho, Somnath Tagore, Gabriel Abril-Rodríguez, Siyu He, Yinuo Jin, Jana Biermann, Matan Hofree, Lindsay Caprio, Simon Berhe, Shaheer A. Khan, Brian S. Henick, Antoni Ribas, Evan Z. Macosko, Fei ChenAlison M. Taylor, Gary K. Schwartz, Richard D. Carvajal, Elham Azizi*, Benjamin Izar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Single-cell genomics enables dissection of tumor heterogeneity and molecular underpinnings of drug response at an unprecedented resolution1–11. However, broad clinical application of these methods remains challenging, due to several practical and preanalytical challenges that are incompatible with typical clinical care workflows, namely the need for relatively large, fresh tissue inputs. In the present study, we show that multimodal, single-nucleus (sn)RNA/T cell receptor (TCR) sequencing, spatial transcriptomics and whole-genome sequencing (WGS) are feasible from small, frozen tissues that approximate routinely collected clinical specimens (for example, core needle biopsies). Compared with data from sample-matched fresh tissue, we find a similar quality in the biological outputs of snRNA/TCR-seq data, while reducing artifactual signals and compositional biases introduced by fresh tissue processing. Profiling sequentially collected melanoma samples from a patient treated in the KEYNOTE-001 trial12, we resolved cellular, genomic, spatial and clonotype dynamics that represent molecular patterns of heterogeneous intralesional evolution during anti-programmed cell death protein 1 therapy. To demonstrate applicability to banked biospecimens of rare diseases13, we generated a single-cell atlas of uveal melanoma liver metastasis with matched WGS data. These results show that single-cell genomics from archival, clinical specimens is feasible and provides a framework for translating these methods more broadly to the clinical arena.

Original languageAmerican English
Pages (from-to)19-25
Number of pages7
JournalNature Genetics
Issue number1
StatePublished - Jan 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.


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