Mesenchymal Cancer Cell-Stroma Crosstalk Promotes Niche Activation, Epithelial Reversion, and Metastatic Colonization.
Loading...
Files
Embargo End Date
ICR Authors
Authors
Del Pozo Martin, Y
Park, D
Ramachandran, A
Ombrato, L
Calvo, F
Chakravarty, P
Spencer-Dene, B
Derzsi, S
Hill, CS
Sahai, E
Malanchi, I
Park, D
Ramachandran, A
Ombrato, L
Calvo, F
Chakravarty, P
Spencer-Dene, B
Derzsi, S
Hill, CS
Sahai, E
Malanchi, I
Document Type
Journal Article
Date
2015-12-06
Date Accepted
2015-11-04
Abstract
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.
Citation
Cell reports, 2015, 13 (11), pp. 2456 - 2469
Source Title
Publisher
ISSN
2211-1247
eISSN
2211-1247
Collections
Research Team
Tumour Microenvironment