Mesenchymal Cancer Cell-Stroma Crosstalk Promotes Niche Activation, Epithelial Reversion, and Metastatic Colonization

• DOI: 10.1016/j.celrep.2015.11.025
• Publication Date: 2015-12-06T13:21:45Z
• Authors: Yaiza del Pozo Ma...; Danielle Park; Anassuya Ramachan...; Luigi Ombrato; Fernando Calvo; Probir Chakravarty; Bradley Spencer-Dene; Stefanie Derzsi; Caroline S. Hill; Erik Sahai; Ilaria Malanchi
• Keywords: 0301 basic medicine; Epithelial-Mesenchymal Transition; Lung Neoplasms; QH301-705.5; Cell Survival; Nude; 610; Mice, Nude; Smad Proteins; Breast Neoplasms; Mice, Transgenic; Transgenic; Article; Cell Line; Mice; 03 medical and health sciences; Transforming Growth Factor beta; Cell Line, Tumor; Proto-Oncogene Proteins; 616; Animals; Humans; Biology (General); Neoplasm Metastasis; Homeodomain Proteins; Transplantation; Heterologous; Tumor; Animal; CD24 Antigen; Receptor Protein-Tyrosine Kinases; Triazoles; 3. Good health; Benzocycloheptenes; Disease Models, Animal; Disease Models; Neoplastic Stem Cells; Female; RNA Interference; Thrombospondins; Signal Transduction

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.