title: Mesenchymal Cancer Cell-Stroma Crosstalk Promotes Niche Activation, Epithelial Reversion, and Metastatic Colonization.
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.
authors.affiliation: Tumor-Stroma Interactions in Cancer Development, The Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, WC2A 3LY London, UK.
authors.forename: Yaiza
authors.initials: Y
authors.lastname: Del Pozo Martin
authors.affiliation: Cell Biology of the Tumor Microenvironment, The Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, WC2A 3LY London, UK.
authors.forename: Danielle
authors.initials: D
authors.lastname: Park
authors.affiliation: 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.
authors.forename: Anassuya
authors.initials: A
authors.lastname: Ramachandran
authors.affiliation: Tumor-Stroma Interactions in Cancer Development, The Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, WC2A 3LY London, UK.
authors.forename: Luigi
authors.initials: L
authors.lastname: Ombrato
authors.affiliation: Tumor Microenvironment Team, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, SW3 6JB London, UK.
authors.forename: Fernando
authors.initials: F
authors.lastname: Calvo
authors.affiliation: Bioinformatics and BioStatistics Team, The Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, WC2A 3LY London, UK.
authors.forename: Probir
authors.initials: P
authors.lastname: Chakravarty
authors.affiliation: Experimental Histopathology Unit, The Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, WC2A 3LY London, UK.
authors.forename: Bradley
authors.initials: B
authors.lastname: Spencer-Dene
authors.affiliation: Cell Biology of the Tumor Microenvironment, The Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, WC2A 3LY London, UK.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Derzsi
authors.affiliation: 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.
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Hill
authors.affiliation: Cell Biology of the Tumor Microenvironment, The Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, WC2A 3LY London, UK.
authors.forename: Erik
authors.initials: E
authors.lastname: Sahai
authors.affiliation: Tumor-Stroma Interactions in Cancer Development, The Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, WC2A 3LY London, UK. Electronic address: ilaria.malanchi@crick.ac.uk.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Malanchi
mesh_terms: D000818:Animals; D001567:Benzocycloheptenes / Q000633:toxicity; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D051927:CD24 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D019699:Thrombospondins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014183:Transplantation, Heterologous; D014230:Triazoles / Q000633:toxicity; D000094963:Axl Receptor Tyrosine Kinase; D000099262:Thrombospondin 2
chemical_list: D001567:Benzocycloheptenes; D051927:CD24 Antigen; D018398:Homeodomain Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D051785:Smad Proteins; D019699:Thrombospondins; D016212:Transforming Growth Factor beta; D014230:Triazoles; D000094963:Axl Receptor Tyrosine Kinase; D000099262:Thrombospondin 2; C548378:bemcentinib; C064658:RAG-1 protein