Spatially resolved transcriptomics reveals the architecture of the tumor-microenvironment interface

Miranda V Hunter,Reuben Moncada,Joshua M Weiss,Itai Yanai,Richard M White

doi:10.1038/s41467-021-26614-z

Abstract

During tumor progression, cancer cells come into contact with various non-tumor cell types, but it is unclear how tumors adapt to these new environments. Here, we integrate spatially resolved transcriptomics, single-cell RNA-seq, and single-nucleus RNA-seq to characterize tumor-microenvironment interactions at the tumor boundary. Using a zebrafish model of melanoma, we identify a distinct “interface” cell state where the tumor contacts neighboring tissues. This interface is composed of specialized tumor and microenvironment cells that upregulate a common set of cilia genes, and cilia proteins are enriched only where the tumor contacts the microenvironment. Cilia gene expression is regulated by ETS-family transcription factors, which normally act to suppress cilia genes outside of the interface. A cilia-enriched interface is conserved in human patient samples, suggesting it is a conserved feature of human melanoma. Our results demonstrate the power of spatially resolved transcriptomics in uncovering mechanisms that allow tumors to adapt to new environments.

Highlights

During tumor progression, cancer cells come into contact with various non-tumor cell types, but it is unclear how tumors adapt to these new environments
We further demonstrate that this distinct “interface” transcriptional state may be conserved in human melanoma, suggesting a conserved mechanism that presents opportunities for halting melanoma invasion and progression
Our results suggest that we have identified a putative “interface” cell state in each of our Spatially resolved transcriptomics (SRT), scRNA-seq, and snRNA-seq datasets, composed of tumor and microenvironment cells which upregulate a common gene program that may contribute to tumor–microenvironment cell interactions at the tumor boundary

Summary

Introduction

Cancer cells come into contact with various non-tumor cell types, but it is unclear how tumors adapt to these new environments. As tumors grow and invade into new tissues, they come into contact with various new cell types, but it is poorly understood how these cell–cell interactions allow for successful invasion and tumor progression. In melanoma, these interactions can occur between the tumor cells and a diverse number of cell types. The microenvironment is increasingly appreciated to play a major role in cancer phenotypes, including proliferation, invasion, metastasis, and drug resistance[5,6] It is debatable whether every cell type that a tumor interacts with is truly part of the microenvironment, since the mechanisms by which these cells influence tumor cell behavior are often unclear. A comprehensive understanding of how tumor and surrounding cells interact in situ is lacking, at least in part due to the limitations of current RNAsequencing technologies

Methods

Results

Conclusion