Stanford team uses Ionpath spatial proteomics in multimodal approach and reveals tumor-specific keratinocyte population at leading edges of squamous cell carcinomas

Multimodal Analysis of Composition and Spatial Architecture in Human Squamous Cell Carcinoma

Ji, et al., Cell  23 Jul 2020: (182), 1-18.

Key Insights

• A new tumor cell subpopulation of tumor-specific keratinocytes (TSKs) was identified and observed to play a key role in intercellular communication
• TSKs were found to reside at the leading edges of carcinoma tissue in fibrovascular niches
• Multiplexed ion beam imaging (MIBI) enabled spatial mapping of tumor, stromal, and immune cells with true single-cell resolution and revealed key intercellular spatial relationships
• A multimodal approach for investigating tumor microenvironments enabled a more comprehensive understanding of tumor biology

Abstract

To define the cellular composition and architecture of cutaneous squamous cell carcinoma (cSCC), Ji et al. combined single-cell RNA sequencing with spatial transcriptomics and multiplexed ion beam imaging (MIBI, a multiplexed spatial proteomics platform) from a series of human cSCCs and matched normal skin. cSCC exhibited four tumor subpopulations, three recapitulating normal epidermal states, and a tumor-specific keratinocyte (TSK) population unique to cancer, which localized to a fibrovascular niche. Integration of single-cell and spatial data mapped ligand-receptor networks to specific cell types, revealing TSK cells as a hub for intercellular communication. Multiple features of potential immunosuppression were observed, including T regulatory cell (Treg) co-localization with CD8 T cells in compartmentalized tumor stroma. Finally, single-cell characterization of human tumor xenografts and in vivo CRISPR screens identified essential roles for specific tumor subpopulation-enriched gene networks in tumorigenesis. These data define cSCC tumor and stromal cell subpopulations, the spatial niches where they interact, and the communicating gene networks that they engage in cancer.