RT Journal Article
SR Electronic
T1 Lung endothelium instructs dormancy of susceptible metastatic tumour cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.06.18.496680
DO 10.1101/2022.06.18.496680
A1 Moritz Jakab
A1 Ki Hong Lee
A1 Alexey Uvarovskii
A1 Svetlana Ovchinnikova
A1 Shubhada R Kulkarni
A1 Till Rostalski
A1 Simon Anders
A1 Hellmut G Augustin
YR 2022
UL http://biorxiv.org/content/early/2022/06/19/2022.06.18.496680.abstract
AB During metastasis, cancer cells hijack blood vessels and travel via the circulation to colonize distant sites1,2. 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 elusive3,4. 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.Competing Interest StatementThe authors have declared no competing interest.