Mesenchymal cancer cell-stroma crosstalk promotes niche activation, epithelial reversion, and metastatic colonization
More about Open Access at the CrickAuthors list
Yaiza del Pozo Martin Danielle Park Anassuya Ramachandran Luigi Ombrato Fernando Calvo Probir Chakravarty Bradley Spencer-Dene Stefanie Derzsi Caroline Hill Erik Sahai Ilaria MalanchiAbstract
During metastatic colonization, tumor cells must establish a favorable microenvironment or niche that will sustain their growth. However, both the temporal and molecular details of this process remain poorly understood. Here, we found that metastatic initiating cells (MICs) exhibit a high capacity for lung fibroblast activation as a result of Thrombospondin 2 (THBS2) expression. Importantly, inhibiting the mesenchymal phenotype of MICs by blocking the epithelial-to-mesenchymal transition (EMT)-associated kinase AXL reduces THBS2 secretion, niche-activating ability, and, consequently, metastatic competence. Subsequently, disseminated metastatic cells revert to an AXL-negative, more epithelial phenotype to proliferate and decrease the phosphorylation levels of TGF-β-dependent SMAD2-3 in favor of BMP/SMAD1-5 signaling. Remarkably, newly activated fibroblasts promote this transition. In summary, our data reveal a crosstalk between cancer cells and their microenvironment whereby the EMT status initially triggers and then is regulated by niche activation during metastatic colonization.
Journal details
Journal Cell Reports
Volume 13
Issue number 11
Pages 2456-2469
Available online
Publication date
Full text links
Publisher website (DOI) 10.1016/j.celrep.2015.11.025
Figshare View on figshare
Europe PubMed Central 26670048
Pubmed 26670048
Keywords
Related topics
Type of publication