Editors' ChoiceCancer

Mapping the tumor frontline

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Science Translational Medicine  15 Jul 2020:
Vol. 12, Issue 552, eabd3609
DOI: 10.1126/scitranslmed.abd3609

Abstract

In cutaneous squamous cell carcinoma, a tumor-specific cell type at the leading edge may drive stromal and immune changes that facilitate progression.

Single-cell RNA sequencing has uncovered dramatic cellular heterogeneity within tumors. However, interpretation of intratumoral heterogeneity has been hampered by the absence of normal control tissue. Furthermore, characterization of the spatial relationships between tumor cell subpopulations has lagged, obfuscating their relevance to tumor biology.

Using cutaneous squamous cell carcinoma (cSCC) as a model, Ji and colleagues have integrated single-cell RNA sequencing (scRNA-seq) with spatial transcriptomics and multiplexed ion beam imaging, revealing a complex interplay of malignant and nonmalignant cells at the tumor edge. The authors performed scRNA-seq on 10 cSCC tumors and site- and patient-matched normal skin. This approach identified four skin cell (keratinocyte) subpopulations, one of which—the tumor-specific keratinocytes (TSKs)—was found only in cSCC and expressed genes associated with invasive behavior. Incorporating spatial data, Ji et al. determined that most TSKs were located at the tumor leading edge where they engaged in extensive cross-talk with adjacent stromal and immune cells to shape the tumor microenvironment (TME) and, the data suggest, suppress anti-tumor immunity. The same four tumor cell subpopulations arose spontaneously when human SCC cell lines were grown in vivo in immunocompromised mice, but not in vitro in tissue culture, demonstrating an essential role for the TME for emergence of this heterogeneity. Using this SCC xenograft system, the authors performed an in vivo CRISPR/Cas9 screen of subpopulation-specific genes and identified a TSK gene network of integrins critical for tumorigenesis. The same genes were less vital for tumor cell culture in vitro by CRISPR screening, suggesting this gene network provides essential protumorigenic communication with the TME. One such gene, FERMT1, was found to be amplified in many cancer subtypes, hinting at a more general role in tumorigenesis. Additionally, higher tumor expression of TSK-associated genes was associated with worse progression-free survival in patients with SCC treated with immune checkpoint inhibitors.

The TME represents a complex ecosystem whose features are difficult to faithfully recapitulate for experimental purposes. In this study, pairing in vivo and in vitro CRISPR screens proved to be a powerful method for uncovering emergent tumorigenic biology. Whether a similar approach would be effective in other cancers such as solid organ malignancies remains to be seen.

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