Spatially Annotated Single Cell Sequencing for Unraveling Intratumor Heterogeneity

Myrthe M. Smit, Kate J. Feller, Li You, Jelle Storteboom, Yasin Begce, Cecile Beerens, Miao Ping Chien*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Scopus)
47 Downloads (Pure)

Abstract

Intratumor heterogeneity is a major obstacle to effective cancer treatment. Current methods to study intratumor heterogeneity using single-cell RNA sequencing (scRNA-seq) lack information on the spatial organization of cells. While state-of-the art spatial transcriptomics methods capture the spatial distribution, they either lack single cell resolution or have relatively low transcript counts. Here, we introduce spatially annotated single cell sequencing, based on the previously developed functional single cell sequencing (FUNseq) technique, to spatially profile tumor cells with deep scRNA-seq and single cell resolution. Using our approach, we profiled cells located at different distances from the center of a 2D epithelial cell mass. By profiling the cell patch in concentric bands of varying width, we showed that cells at the outermost edge of the patch responded strongest to their local microenvironment, behaved most invasively, and activated the process of epithelial-to-mesenchymal transition (EMT) to migrate to low-confluence areas. We inferred cell-cell communication networks and demonstrated that cells in the outermost ∼10 cell wide band, which we termed the invasive edge, induced similar phenotypic plasticity in neighboring regions. Applying FUNseq to spatially annotate and profile tumor cells enables deep characterization of tumor subpopulations, thereby unraveling the mechanistic basis for intratumor heterogeneity.

Original languageEnglish
Article number829509
JournalFrontiers in Bioengineering and Biotechnology
Volume10
DOIs
Publication statusPublished - 22 Feb 2022

Bibliographical note

ACKNOWLEDGEMENTS
M-PC acknowledges support from the Oncode Institute, Cancer GenomiCs.nl (CGC), NWO (Netherlands Organization for
Scientific Research) Veni Grant, Stichting Ammodo and Erasmus MC grant. M-PC appreciates Josephine Nefkens
Stichting’s support on the UFO microscope. We thank Reuven Agami for the kind gift of the MCF10A-H2B-GFP cell line.

Publisher Copyright:
Copyright © 2022 Smit, Feller, You, Storteboom, Begce, Beerens and Chien.

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