title: ADAMTS1 contributes to the acquisition of an endothelial-like phenotype in plastic tumor cells.
abstract: Cancer stem cells have been hypothesized to explain tumor plasticity, including the capability to adopt distinct differentiation commitments. Among the mechanisms of tumor neovascularization, the ability of some malignant cells to mimic an endothelial phenotype has been recognized by a capacity to form matrix-enriched pseudovascular structures. In addition to the expression of genes associated with an endothelial nature, the molecular dynamism of specific microenvironments may also be critical. Here, we report the identification of the extracellular protease ADAMTS1 as a critical molecule for tumor cells to acquire endothelial-like properties. In a fibrosarcoma model, ADAMTS1 increased tumor growth rate in an angiogenesis-independent manner, influencing the tumor cells to display an exclusive endothelial-like gene signature. We documented the relevant expression of ADAMTS1 in aggressive and highly plastic melanoma and Ewing sarcoma cells. Notably, inhibiting ADAMTS1 action compromised the endothelial mimetic attributes observed in this setting. Our findings provide insights into how the tumor microenvironment can elicit endothelial mimicry by tumor cells.
authors.affiliation: GENYO (Pfizer-University of Granada-Andalusian Government Centre for Genomics and Oncological Research), Armilla, Granada, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Casal
authors.forename: Antoni Xavier
authors.initials: AX
authors.lastname: Torres-Collado
authors.forename: María Del Carmen
authors.initials: Mdel C
authors.lastname: Plaza-Calonge
authors.forename: Estefanía
authors.initials: E
authors.lastname: Martino-Echarri
authors.forename: Santiago
authors.initials: S
authors.lastname: Ramón Y Cajal
authors.forename: Federico
authors.initials: F
authors.lastname: Rojo
authors.forename: Arjan W
authors.initials: AW
authors.lastname: Griffioen
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Rodríguez-Manzaneque
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D000071097:ADAMTS1 Protein; D000818:Animals; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000201:enzymology / Q000473:pathology; D005354:Fibrosarcoma / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D012512:Sarcoma, Ewing / Q000201:enzymology* / Q000473:pathology*; D014183:Transplantation, Heterologous
chemical_list: D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; C103859:ADAMTS1 protein, human