On the TRAIL of Better Therapies: Understanding TNFRSF Structure-Function

Vanamee, Eva; Faustman, Denise L.

doi:10.3390/cells9030764

Cited by 26 publications

(22 citation statements)

References 52 publications

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“…21 d after injection, lung metastases were determined (G). a higher-order signaling complex mediated by TNFR-associated factor dimerization and trimerization interfaces (Napetschnig and Wu, 2013;Vanamee and Faustman, 2020).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ADAM17 impairs endothelial cell necroptosis and blocks metastasis

Bolik

Krause

Stevanovic

et al. 2021

Journal of Experimental Medicine

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Metastasis is the major cause of death in cancer patients. Circulating tumor cells need to migrate through the endothelial layer of blood vessels to escape the hostile circulation and establish metastases at distant organ sites. Here, we identified the membrane-bound metalloprotease ADAM17 on endothelial cells as a key driver of metastasis. We show that TNFR1-dependent tumor cell–induced endothelial cell death, tumor cell extravasation, and subsequent metastatic seeding is dependent on the activity of endothelial ADAM17. Moreover, we reveal that ADAM17-mediated TNFR1 ectodomain shedding and subsequent processing by the γ-secretase complex is required for the induction of TNF-induced necroptosis. Consequently, genetic ablation of ADAM17 in endothelial cells as well as short-term pharmacological inhibition of ADAM17 prevents long-term metastases formation in the lung. Thus, our data identified ADAM17 as a novel essential regulator of necroptosis and as a new promising target for antimetastatic and advanced-stage cancer therapies.

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Section: Discussionmentioning

confidence: 99%

Inhibition of ADAM17 impairs endothelial cell necroptosis and blocks metastasis

Bolik

Krause

Stevanovic

et al. 2021

Journal of Experimental Medicine

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“…Binding of TNFα to the TNFR1 eventually leads to caspase or NF-κB activation ( Faustman and Davis, 2010 ; Brenner et al., 2015 ), whereas trimeric activation of Fas, TrailR1/2 complexes selectively induces caspase-mediated apoptosis (David R. McIlwain et al., 2015 ; E. M. Creagh and Martin, 2001 ). Recent data suggests also higher-than-trimeric receptor oligomerization upon activation ( Vanamee and Faustman, 2020 ), comparable to cluster-activation seen for T-cell receptors ( Grakoui et al., 1999 ). Targeted analysis of TNFRSF members is also of importance, because mutations in TNFSF/TNFRSF members can lead to various diseases among them, such as TNF receptor-associated periodic syndrome (TRAPS) ( Savic et al., 2012 ) or autoimmune lymphoproliferative syndrome (ALPS) (Anke M.J. Peters et al., 1999 ).…”

Section: Introductionmentioning

confidence: 78%

“…Here, we could see that apoptosis induced by FasL dimers is carried out slower than apoptosis of trimeric or hexameric FasL. Recent studies showed that Fas receptors are arranged as antiparallel dimers that form overall hexagonal lattices without the ligand (Vanamee and Faustman, 2018a;Vanamee and Faustman, 2020). This arrangement is necessary for the appropriate DISC formation and interaction with FADD upon ligand binding.…”

Section: Ll Open Access Isciencementioning

confidence: 88%

Pro- and anti-apoptotic fate decisions induced by di- and trimeric synthetic cytokine receptors

2021

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Summary Synthetic strategies to activate cytokine receptors so far only address standard dimeric cytokine receptor assemblies. The 19 ligands of the tumor necrosis factor superfamily (TNFSF), however, form noncovalent trimers and receptor trimerization is considered to be essential for receptor activation. Synthetic TNFR1, TNFR2, and Fas/CD95 receptors were activated by synthetic trimeric ligands which induced NF-κB signaling or Caspase-induced apoptosis. Albeit dimeric receptor activation did not induce synthetic TNFR1 and TNFR2 signaling, dimeric FasL induced extenuated apoptosis. Simultaneous integration of dimeric Interleukin (IL-)6 receptor gp130 and trimeric Fas as synthetic cytokine receptors in one cell enabled binary cell fate decisions, gp130-mediated proliferation or Fas-mediated apoptosis. In summary, our modular fully synthetic cytokine signaling system allows precisely orchestrated cellular responses to selectively induce pro- and anti-apoptotic signaling via canonical dimeric receptors of the IL-6 family and non-canonical trimeric receptor complexes of the TNF superfamily.

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“…In general, there was a significant upregulation of genes previously demonstrated to have anti-tumor activity and downregulation of many having pro-tumor involvement. For example, TNF-related apoptosis-inducing ligand (TRAIL) is a potent stimulator of apoptosis, especially on tumor cells, making them excellent therapeutic targets for cancer ( 74 ). Cytotoxic ADMC upregulated several TRAIL receptors (e.g.…”

Section: Discussionmentioning

confidence: 99%

Human Tumor Targeted Cytotoxic Mast Cells for Cancer Immunotherapy

et al. 2022

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The diversity of autologous cells being used and investigated for cancer therapy continues to increase. Mast cells (MCs) are tissue cells that contain a unique set of anti-cancer mediators and are found in and around tumors. We sought to exploit the anti-tumor mediators in MC granules to selectively target them to tumor cells using tumor specific immunoglobin E (IgE) and controllably trigger release of anti-tumor mediators upon tumor cell engagement. We used a human HER2/neu-specific IgE to arm human MCs through the high affinity IgE receptor (FcεRI). The ability of MCs to bind to and induce apoptosis of HER2/neu-positive cancer cells in vitro and in vivo was assessed. The interactions between MCs and cancer cells were investigated in real time using confocal microscopy. The mechanism of action using cytotoxic MCs was examined using gene array profiling. Genetically manipulating autologous MC to assess the effects of MC-specific mediators have on apoptosis of tumor cells was developed using siRNA. We found that HER2/neu tumor-specific IgE-sensitized MCs bound, penetrated, and killed HER2/neu-positive tumor masses in vitro. Tunneling nanotubes formed between MCs and tumor cells are described that parallel tumor cell apoptosis. In solid tumor, human breast cancer (BC) xenograft mouse models, infusion of HER2/neu IgE-sensitized human MCs co-localized to BC cells, decreased tumor burden, and prolonged overall survival without indications of toxicity. Gene microarray of tumor cells suggests a dependence on TNF and TGFβ signaling pathways leading to apoptosis. Knocking down MC-released tryptase did not affect apoptosis of cancer cells. These studies suggest MCs can be polarized from Type I hypersensitivity-mediating cells to cytotoxic cells that selectively target tumor cells and specifically triggered to release anti-tumor mediators. A strategy to investigate which MC mediators are responsible for the observed tumor killing is described so that rational decisions can be made in the future when selecting which mediators to target for deletion or those that could further polarize them to cytotoxic MC by adding other known anti-tumor agents. Using autologous human MC may provide further options for cancer therapeutics that offers a unique anti-cancer mechanism of action using tumor targeted IgE’s.

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On the TRAIL of Better Therapies: Understanding TNFRSF Structure-Function

Cited by 26 publications

References 52 publications

Inhibition of ADAM17 impairs endothelial cell necroptosis and blocks metastasis

Inhibition of ADAM17 impairs endothelial cell necroptosis and blocks metastasis

Pro- and anti-apoptotic fate decisions induced by di- and trimeric synthetic cytokine receptors

Human Tumor Targeted Cytotoxic Mast Cells for Cancer Immunotherapy

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