Mesenchymal Cancer Cell-Stroma Crosstalk Promotes Niche Activation, Epithelial Reversion, and Metastatic Colonization
Yaiza del Pozo Martin,
Danielle Park,
Anassuya Ramachandran,
Luigi Ombrato,
Fernando Calvo,
Probir Chakravarty,
Bradley Spencer-Dene,
Stefanie Derzsi,
Caroline S. Hill,
Erik Sahai,
Ilaria Malanchi
Affiliations
Yaiza del Pozo Martin
Tumor-Stroma Interactions in Cancer Development, The Crick Institute, Lincoln’s Inn Fields Laboratory, 44 Lincoln’s Inn Fields, WC2A 3LY London, UK
Danielle Park
Cell Biology of the Tumor Microenvironment, The Crick Institute, Lincoln’s Inn Fields Laboratory, 44 Lincoln’s Inn Fields, WC2A 3LY London, UK
Anassuya Ramachandran
TGF-β Superfamily Signalling in Development and Cancer, The Crick Institute, Lincoln’s Inn Fields Laboratory, 44 Lincoln’s Inn Fields, WC2A 3LY London, UK
Luigi Ombrato
Tumor-Stroma Interactions in Cancer Development, The Crick Institute, Lincoln’s Inn Fields Laboratory, 44 Lincoln’s Inn Fields, WC2A 3LY London, UK
Fernando Calvo
Tumor Microenvironment Team, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, SW3 6JB London, UK
Probir Chakravarty
Bioinformatics and BioStatistics Team, The Crick Institute, Lincoln’s Inn Fields Laboratory, 44 Lincoln’s Inn Fields, WC2A 3LY London, UK
Bradley Spencer-Dene
Experimental Histopathology Unit, The Crick Institute, Lincoln’s Inn Fields Laboratory, 44 Lincoln’s Inn Fields, WC2A 3LY London, UK
Stefanie Derzsi
Cell Biology of the Tumor Microenvironment, The Crick Institute, Lincoln’s Inn Fields Laboratory, 44 Lincoln’s Inn Fields, WC2A 3LY London, UK
Caroline S. Hill
TGF-β Superfamily Signalling in Development and Cancer, The Crick Institute, Lincoln’s Inn Fields Laboratory, 44 Lincoln’s Inn Fields, WC2A 3LY London, UK
Erik Sahai
Cell Biology of the Tumor Microenvironment, The Crick Institute, Lincoln’s Inn Fields Laboratory, 44 Lincoln’s Inn Fields, WC2A 3LY London, UK
Ilaria Malanchi
Tumor-Stroma Interactions in Cancer Development, The Crick Institute, Lincoln’s Inn Fields Laboratory, 44 Lincoln’s Inn Fields, WC2A 3LY London, UK
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.
