Basement membrane remodeling is essential for Drosophila disc eversion and tumor invasion.
Organ and tissue integrity is often maintained in animals by a specialized extracellular matrix structure called the basement membrane (BM). Accumulated evidence indicates that BM remodeling occurs during development and tumor invasion. Although the BM organizes and functions at the organ level, most past studies have explored its biochemical and in vitro properties. In this study, we monitor the BM in vivo during developmental tissue invasion for disc eversion and tumor invasion in Drosophila and modulate BM integrity with genetic alterations affecting either the whole organism or the targeted discs or tumors. We observe that the degradation of BM by the discs or the tumors is an early event during invasion processes and that preventing BM degradation completely blocks both tissue and tumor invasion, indicating that modulation of BM is essential for developmental and tumor invasion. Furthermore, elements of the invasion machinery, including JNK-induced matrix metalloproteinase (MMP) expression, are shared by both disc eversion and tumor invasion processes. Moreover, we show that although expression of MMP inhibitor, TIMP, is sufficient to halt developmental invasion, inhibition of proteases by both TIMP and RECK are required to block tumor invasion. These data suggest that tumor cells have a more robust invasion mechanism and could acquire metastatic behavior by co-opting developmental invasion programs. This type of co-option may be a general feature contributing to the progression of tumors. Finally, although past efforts using MMP inhibitors have not yielded much success, our results strongly argue that BM modulation could be a critical target for cancer therapy.
Srivastava
Ajay
A
Department of Genetics and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
Pastor-Pareja
Jose Carlos
JC
Igaki
Tatsushi
T
Pagliarini
Raymond
R
Xu
Tian
T
D000818:Animals; D001485:Basement Membrane / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000196:embryology* / Q000201:enzymology; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008954:Models, Biological; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology*; D011679:Pupa / Q000166:cytology; D015398:Signal Transduction; D014921:Wings, Animal / Q000002:abnormalities / Q000166:cytology / Q000196:embryology*
D048031:JNK Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases