Basement membrane remodeling is essential for Drosophila disc eversion and tumor invasion

Abstract

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.developmental invasion ͉ JNK signaling ͉ tumor metastasis ͉ matrix metalloproteinase

Identification of Novel Ras-Cooperating Oncogenes in Drosophila melanogaster: A RhoGEF/Rho-Family/JNK Pathway Is a Central Driver of Tumorigenesis

“…The effect of JNK on invasion has been shown to be due to upregulation of targets important in cell migration, such as Paxillin, and in breakdown of the extracellular matrix, such as MMP1 (Beaucher et al 2006;Uhlirova and Bohmann 2006;Srivastava et al 2007;Leong et al 2009), but how JNK blocks differentiation and pupation is currently unknown. Expression of bsk DN also reduced tumor overgrowth to a level commensurate with Ras ACT alone for all except Rac1 1 Ras ACT .…”

Tumor suppressor roles of CENP-E and Nsl1 inDrosophilaepithelial tissues

“…While Wg is an absolute requirement for CIN-induced tissue overgrowth, 10 MMPs are well-known to contribute to BM degradation both in flies and mammals. [24][25][26] We thus monitored the expression of these 2 JNK targets in tissues depleted of CENP-E or Nsl1. In wild-type wing primordia, Wg is expressed in a stripe that corresponds to the future wing margin (Fig.…”

Epithelial delamination and migration

“…In this context, JNK signaling directs growth and invasion instead of promoting cell death. 39,[53][54][55][56] Importantly, Ras can cooperate with other oncogenic pathways that result in JNK activation without directly regulating cell polarity, such as Src 50 and Rho-family GTPases. 57 Remarkably, because JNK activation propagates across imaginal disc epithelia, the cooperation between JNK and Ras does not need to be cell autonomous.…”

“…37 Many aspects of human tumorogenesis are recapitulated in mutants of a class of Tumor Suppressor Genes (TSGs) coding for proteins involved in the establishment of apical-basal polarity of epithelial cells. 38,39 These Drosophila tumor models display a loss of cellular architecture, dramatic over-proliferation, basal membrane (BM) degradation and invasive capacity. 39,40 In this context Pastor-Pareja and coworkers investigated the role of the cellular immune system in cancer detection and surveillance and found hemocytes adhered to the tumor surface at the site of BM disruption.…”

“…38,39 These Drosophila tumor models display a loss of cellular architecture, dramatic over-proliferation, basal membrane (BM) degradation and invasive capacity. 39,40 In this context Pastor-Pareja and coworkers investigated the role of the cellular immune system in cancer detection and surveillance and found hemocytes adhered to the tumor surface at the site of BM disruption. 41 In tumor-bearing flies, the increase in hemocyte number-as a consequence of secretion of JAK-STAT activating cytokines by the tumor cells-was suggested to be the means to restrict tumor growth.…”