Lung endothelium instructs dormancy of susceptible metastatic tumour cells

Abstract

During metastasis, cancer cells hijack blood vessels and travel via the circulation to colonize distant sites. Due to the rarity of these events, the immediate cell fate decisions of arrested circulating tumour cells (aCTC) are poorly understood and the role of the endothelium, as the interface of dissemination, remains elusive. Here, we developed a novel strategy to specifically enrich for aCTC subpopulations capturing all cell states of the extravasation process and, in combination with single cell RNA-sequencing, provide a first blueprint of the transcriptional basis of early aCTC decisions. Upon their arrest at the metastatic site, tumour cells either started proliferating intravascularly or extravasated and preferably reached a state of quiescence. Endothelial-derived angiocrine Wnt factors were found to drive this bifurcation by inducing a mesenchymal-like phenotype in aCTCs instructing them to follow the extravasation-dormancy branch. Surprisingly, homogenous tumour cell pools showed an unexpected baseline heterogeneity in Wnt signalling activity and epithelial-to-mesenchyme-transition (EMT) states. This heterogeneity was established at the epigenetic level and served as the driving force of aCTC behaviour. Hypomethylation enabled high baseline Wnt and EMT activity in tumour cells leading them to preferably follow the extravasation-dormancy route, whereas methylated tumour cells had low activity and proliferated intravascularly. The data identify the pre-determined methylation status of disseminated tumour cells as a key regulator of aCTC behaviour in the metastatic niche. While metastatic niche-derived factors per default instruct the acquisition of quiescence, aCTCs unwind a default proliferation program and only deviate from it if hypomethylation in key gene families renders them responsive towards the microenvironment.

Identification of astrocyte-driven pseudolineages reveals clinical stratification and therapeutic targets in Glioblastoma

“…This contrast highlights the unique characteristics of ventricular outgrowths, potentially explaining the aggressive disease progression in patients with ventricular tumors 60 . Such a mechanism would be consistent with metastatic cells at the vessel lumen, where cWnt activity is only gained upon extravasation and triggers a proliferative-to-dormant switch 61 . Consequently, investigating Wnt activity in luminal outgrowths of colon cancer might reveal that these sites are insensitive to Wnt inhibition.…”

Endothelial Pim3 kinase protects the vascular barrier during lung metastasis

“…In distant metastasis, invasive cancer cells leave the primary tumor and travel via the blood or lymphatic vessels to colonize distant tissues or lymph nodes, respectively 1 . Circulating tumor cells become entrapped within organ-specific capillaries before crossing the capillary wall into the tissue, initiating genetic programs of metastatic growth or remaining dormant [2][3][4] . Metastatic growth is dependent on interactions between tumor cells and their microenvironment, the niche, which consists of heterotypic cells including immune cells and endothelial cells (ECs), among others 5 .…”