Abstract
Malignant cell growth is fueled by interactions between tumor cells and the stromal cells composing the tumor microenvironment. The human liver is a major site of tumors and metastases, but molecular identities and intercellular interactions of different cell types have not been resolved in these pathologies. Here, we apply single cell RNA‐sequencing and spatial analysis of malignant and adjacent non‐malignant liver tissues from five patients with cholangiocarcinoma or liver metastases. We find that stromal cells exhibit recurring, patient‐independent expression programs, and reconstruct a ligand–receptor map that highlights recurring tumor–stroma interactions. By combining transcriptomics of laser‐capture microdissected regions, we reconstruct a zonation atlas of hepatocytes in the non‐malignant sites and characterize the spatial distribution of each cell type across the tumor microenvironment. Our analysis provides a resource for understanding human liver malignancies and may expose potential points of interventions.
Highlights
Cancer is a heterogeneous disease, exhibiting both interpatient and intrapatient variability (Marusyk et al, 2012; Meacham & Morrison, 2013; Patel et al, 2014; Alizadeh et al, 2015)
The cells formed 17 clusters, which we annotated based on known marker genes and a recent cell atlas of cirrhotic human livers (Ramachandran et al, 2019) (Fig 1C)
Genes elevated in colorectal cancer metastasis included higher expression of Cadherin 17 (CDH17) (Panarelli et al, 2012) and the adhesion molecules CEACAM5 and CEACAM6, previously shown to correlate with metastasis colonization (Powell et al, 2018)
Summary
Cancer is a heterogeneous disease, exhibiting both interpatient and intrapatient variability (Marusyk et al, 2012; Meacham & Morrison, 2013; Patel et al, 2014; Alizadeh et al, 2015). Tumor cells do not operate in isolation, but rather closely interact with a complex milieu of supporting stromal cells that form the tumor microenvironment (TME) (Polyak et al, 2009; Hanahan & Weinberg, 2011; Lambrechts et al, 2018). These cells include, among others, a range of immune cells, cancer-associated fibroblasts (CAFs), and endothelial cells. Interactions between the tumor and stromal cells are critical for cancer cell survival (Meacham & Morrison, 2013). Given the diversity of cell types that form the TME, it is essential to apply single cell approaches to resolve their molecular identities (Tirosh et al, 2016; Puram et al, 2017; Lambrechts et al, 2018)
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