Mesenchymal Cancer Cell-Stroma Crosstalk Promotes Niche Activation, Epithelial Reversion, and Metastatic Colonization.
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Date
2015-12-06ICR Author
Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Cell Line, Tumor
Animals
Mice, Transgenic
Humans
Mice
Mice, Nude
Breast Neoplasms
Lung Neoplasms
Neoplasm Metastasis
Disease Models, Animal
Triazoles
Benzocycloheptenes
Receptor Protein-Tyrosine Kinases
Transforming Growth Factor beta
Homeodomain Proteins
Thrombospondins
Proto-Oncogene Proteins
Transplantation, Heterologous
Signal Transduction
Cell Survival
RNA Interference
Female
Smad Proteins
Neoplastic Stem Cells
Epithelial-Mesenchymal Transition
CD24 Antigen
Research team
Tumour Microenvironment
Language
eng
Date accepted
2015-11-04
License start date
2015-12-06
Citation
Cell reports, 2015, 13 (11), pp. 2456 - 2469