skip to primary navigationskip to content
 

Why the microenvironment matters

last modified Jul 06, 2020 03:04 PM

Single cell RNA-sequencing reveals a dynamic stromal niche that supports tumour growth

Cancer cells are surrounded by a diverse range of “normal cells” known as the stroma. The stroma includes immune cells, endothelial cells, fibroblasts and the extracellular matrix scaffold they produce. Together cancer cells and stroma form the tumour microenvironment. Crosstalk between the tumour and stroma is critical to help a tumour form and grow, but the complex relationships that exist within such a rapidly changing microenvironment remain unclear. In their recent paper published in Cell Reports, Davidson et al from the Shields lab, in collaboration with  Sarah Teichmann’s lab (Wellcome Trust Sanger Institute) used single cell RNA sequencing (scRNAseq) to resolve stromal heterogeneity at the single-cell level, and to characterize how the function of stromal cells is temporally regulated during carcinogenesis. They showed that immune cells enter the tumour in a naïve state, where they are educated to develop immune suppressive functions. Researchers also identified the existence of fibroblast populations with distinct functions; immune regulatory, desmoplastic (laying down and remodelling extracellular matrix) and contractile. Contractile populations dominated in later, more established tumours. However, fibroblasts with immune regulatory function were prevalent at earliest stages of tumour development examined, producing factors to attract immune cells and change their function.

While previous single cell studies have examined the tumour from individual time points, this study uses this technology to characterise the changing stromal landscape within a developing tumour microenvironment and associated lymph nodes in real time. This approach has given rise to a new level insight into the populations, dynamics and interactions occurring in order to meet the changing requirements of a rapidly growing tumour. As part of the study, having collected such a large dataset, the researchers employed a unique database of known ligand-receptor interactions developed in the Teichmann Lab. With this approach, they were able to identify potential interactions across stromal and immune populations to predict interactions that support tumour growth. Indeed, these predictions were used to disrupt specific interactions between fibroblasts and macrophages in preclinical cancer models and showed a slowing of tumour growth. All data is freely available at data.teichlab.org.

Collectively, the results highlight the power of scRNAseq to identify complex interplays and increasing stromal diversity as tumours develop, and serve as a resource for identifying candidates with therapeutic potential. This sets the foundation for further investigation of stromal kinetics in human tumours to develop potential patient stratification approaches and identification of novel stromal focussed-therapeutic strategies.