Stroma-derived but not tumor ADAMTS1 is a main driver of tumor growth and metastasis.
The matrix metalloprotease ADAMTS1 (A Disintegrin And Metalloprotease with ThromboSpondin repeats 1) has been involved in tumorigenesis although its contributions appeared ambiguous. To understand the multifaceted actions of this protease, it is still required a deeper knowledge of its implication in heterogeneous tumor-stroma interactions. Using a syngeneic B16F1 melanoma model in wild type and ADAMTS1 knockout mice we found distinct stroma versus tumor functions for this protease. Genetic deletion of ADAMTS1 in the host microenvironment resulted in a drastic decrease of tumor growth and metastasis. However, the downregulation of tumor ADAMTS1 did not uncover relevant effects. Reduced tumors in ADAMTS1 KO mice displayed a paradoxical increase in vascular density and vascular-related genes; a detailed characterization revealed an impaired vasculature, along with a minor infiltration of macrophages. In addition, ex-vivo assays supported a chief role for ADAMTS1 in vascular sprouting, and melanoma xenografts showed a relevant induction of its expression in stroma compartments. These findings provide the first genetic evidence that supports the pro-tumorigenic role of stromal ADAMTS1.
GENYO, Centre for Genomics and Oncological Research, Pfizer/Universidad de Granada/Junta de Andalucía, Granada 18016, Spain.
Rubén
R
Fernández-Rodríguez
GENYO, Centre for Genomics and Oncological Research, Pfizer/Universidad de Granada/Junta de Andalucía, Granada 18016, Spain.
Francisco Javier
FJ
Rodríguez-Baena
GENYO, Centre for Genomics and Oncological Research, Pfizer/Universidad de Granada/Junta de Andalucía, Granada 18016, Spain.
Estefanía
E
Martino-Echarri
GENYO, Centre for Genomics and Oncological Research, Pfizer/Universidad de Granada/Junta de Andalucía, Granada 18016, Spain.
Carlos
C
Peris-Torres
GENYO, Centre for Genomics and Oncological Research, Pfizer/Universidad de Granada/Junta de Andalucía, Granada 18016, Spain.
María
M
Del Carmen Plaza-Calonge
GENYO, Centre for Genomics and Oncological Research, Pfizer/Universidad de Granada/Junta de Andalucía, Granada 18016, Spain.
Juan Carlos
JC
Rodríguez-Manzaneque
D000071097:ADAMTS1 Protein / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015536:Down-Regulation; D017353:Gene Deletion; D057809:HEK293 Cells; D006801:Humans; D008264:Macrophages / Q000276:immunology; D008545:Melanoma / Q000473:pathology*; D008546:Melanoma, Experimental / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009362:Neoplasm Metastasis / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000473:pathology*; D014604:Uveal Neoplasms / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays; D000098943:Uveal Melanoma
D000071097:ADAMTS1 Protein; C486323:Adamts1 protein, mouse
extracellular matrix; extracellular protease; hypoxia; tumor stroma; vasculature