Targeting matriptase in breast cancer abrogates tumour progression via impairment of stromal-epithelial growth factor signalling

Zoratti, Gina L.; Tanabe, Lauren M.; Varela, Fausto A.; Murray, Andrew S.; Bergum, Christopher; Colombo, Éloïc; Lang, Julie E.; Molinolo, Alfredo A.; Leduc, Richard; Marsault, Éric; Boerner, Julie L.; List, Karin

doi:10.1038/ncomms7776

Cited by 52 publications

(60 citation statements)

References 54 publications

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“…In the polyoma middle T antigen-induced breast cancer model, genetic or pharmacological inhibition of TF, matriptase, and PAR2 all blunt tumor growth. 29,[76][77][78] Matriptase plays a critical role in pro-HGF activation and c-Met signaling in this model. 77 The role for coagulation proteases in matriptase activation, the importance of matriptase for PAR2 activation, and relative roles of PAR2 and HGF downstream of matriptase remain to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…29,[76][77][78] Matriptase plays a critical role in pro-HGF activation and c-Met signaling in this model. 77 The role for coagulation proteases in matriptase activation, the importance of matriptase for PAR2 activation, and relative roles of PAR2 and HGF downstream of matriptase remain to be determined. Matriptase activation by coagulation proteases argues that pro-HGF, pro-urokinase, and other matriptase substrates should be considered alongside PARs and fibrin downstream of TF in tumor growth and dissemination.…”

Section: Discussionmentioning

confidence: 99%

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Matriptase activation connects tissue factor–dependent coagulation initiation to epithelial proteolysis and signaling

Gall

Szabo

Lee

et al. 2016

Blood

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The coagulation cascade is designed to sense tissue injury by physical separation of the membrane-anchored cofactor tissue factor (TF) from inactive precursors of coagulation proteases circulating in plasma. Once TF on epithelial and other extravascular cells is exposed to plasma, sequential activation of coagulation proteases coordinates hemostasis and contributes to host defense and tissue repair. Membrane-anchored serine proteases (MASPs) play critical roles in the development and homeostasis of epithelial barrier tissues; how MASPs are activated in mature epithelia is unknown. We here report that proteases of the extrinsic pathway of blood coagulation transactivate the MASP matriptase, thus connecting coagulation initiation to epithelial proteolysis and signaling. Exposure of TF-expressing cells to factors (F) VIIa and Xa triggered the conversion of latent pro-matriptase to an active protease, which in turn cleaved the pericellular substrates protease-activated receptor-2 (PAR2) and pro-urokinase. An activation pathway-selective PAR2 mutant resistant to direct cleavage by TF:FVIIa and FXa was activated by these proteases when cells co-expressed pro-matriptase, and matriptase transactivation was necessary for efficient cleavage and activation of wild-type PAR2 by physiological concentrations of TF:FVIIa and FXa. The coagulation initiation complex induced rapid and prolonged enhancement of the barrier function of epithelial monolayers that was dependent on matriptase transactivation and PAR2 signaling. These observations suggest that the coagulation cascade engages matriptase to help coordinate epithelial defense and repair programs after injury or infection, and that matriptase may contribute to TF-driven pathogenesis in cancer and inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Matriptase activation connects tissue factor–dependent coagulation initiation to epithelial proteolysis and signaling

Gall

Szabo

Lee

et al. 2016

Blood

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show abstract

“…The role of matriptase in vivo has also been studied in detail in breast cancer. In an oncogene-induced mouse mammary carcinoma model, hypomorphic matriptase mice with reduced levels of matriptase displayed a significant delay in tumor formation and blunted tumor growth (Zoratti et al, 2015). The reduced tumor growth was associated with a profound decrease in cancer cell proliferation.…”

Section: Matriptasementioning

confidence: 99%

“…Mechanistic studies demonstrated that the proliferation deficiency was caused by the impairment of carcinoma cells, in cell lines and in vivo, to initiate the activation of the c-Met signaling pathway in response to fibroblast-secreted pro-hepatocyte growth factor (pro-HGF) (Figure 1). In primary mammary carcinoma cells and human breast cancer cell lines, addition of HAI-1 and HAI-2 inhibited pro-HGF mediated c-Met signaling and cell proliferation (Zoratti et al, 2015). Importantly, inhibition of matriptase catalytic activity using a selective small-molecule inhibitor efficiently abrogates the activation of c-Met, Gab1 and AKT, in response to pro-HGF, which functionally leads to attenuated cancer cell proliferation and invasion.…”

Section: Matriptasementioning

confidence: 99%

Type II transmembrane serine proteases as potential targets for cancer therapy

Murray

Varela

List

2016

Biological Chemistry

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Carcinogenesis is accompanied by increased protein and activity levels of extracellular cell-surface proteases that are capable of modifying the tumor micro-environment by directly cleaving the extracellular matrix, as well as activating growth factors and proinflammatory mediators involved in proliferation and invasion of cancer cells, and recruitment of inflammatory cells. These complex processes ultimately potentiate neoplastic progression leading to local tumor cell invasion, entry into the vasculature, and metastasis to distal sites. Several members of the type II transmembrane serine protease (TTSP) family have been shown to play critical roles in cancer progression. In this review the knowledge collected over the past two decades about the molecular mechanisms underlying the pro-cancerous properties of selected TTSPs will be summarized. Furthermore, we will discuss how these insights may facilitate the translation into clinical settings in the future by specifically targeting TTSPs as part of novel cancer treatment regimens.

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“…First successful proof of concepts studies with prostate cancer models in mice have been performed with the arginal-derived matriptase inhibitor CVS-3983 pancreatic adenocarcinoma cell line AsPC-1 21 . Even stronger effects on pro-HGF/SF induced c-Met activation on primary mammary carcinoma cells and three other human breast cancer cell lines were described for the ketobenzothiazole inhibitor IN-1 22 ( Figure 1), meanwhile various highly potent ketonederived inhibitors have been described 23,24 . The invasiveness and migration of various tumor cell lines could be also inhibited by other benzamidine-derived matriptase inhibitors 25,26 .…”

Section: Introductionmentioning

confidence: 99%

Changing the selectivity profile – from substrate analog inhibitors of thrombin and factor Xa to potent matriptase inhibitors

Maiwald

Hammami

Wagner

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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The type II transmembrane serine protease matriptase is a potential target for anticancer therapy and might be involved in cartilage degradation in osteoarthritis or inflammatory skin disorders. Starting from previously described nonspecific thrombin and factor Xa inhibitors we have prepared new noncovalent substrate-analogs with superior potency against matriptase. The most suitable compound 35 (H-D-hTyr-Ala-4-amidinobenzylamide) binds to matriptase with an inhibition constant of 26 nM and has more than 10-fold reduced activity against thrombin and factor Xa. The crystal structure of inhibitor 35 was determined in the surrogate protease trypsin, the obtained complex was used to model the binding mode of inhibitor 35 in the active site of matriptase. The methylene insertion in D-hTyr and D-hPhe increases the flexibility of the P3 side chain compared to their D-Phe analogs, which enables an improved binding of these inhibitors in the well-defined S3/4 pocket of matriptase. Inhibitor 35 can be used for further biochemical studies with matriptase.

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Targeting matriptase in breast cancer abrogates tumour progression via impairment of stromal-epithelial growth factor signalling

Cited by 52 publications

References 54 publications

Matriptase activation connects tissue factor–dependent coagulation initiation to epithelial proteolysis and signaling

Matriptase activation connects tissue factor–dependent coagulation initiation to epithelial proteolysis and signaling

Type II transmembrane serine proteases as potential targets for cancer therapy

Changing the selectivity profile – from substrate analog inhibitors of thrombin and factor Xa to potent matriptase inhibitors

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