ADAM17 is required for EGF-R–induced intestinal tumors via IL-6 trans-signaling

Schmidt, Stefanie; Schumacher, Neele; Schwarz, Jeanette; Tangermann, Simone; Kenner, Lukas; Schlederer, Michaela; Sibilia, Maria; Linder, Markus; Altendorf-Hofmann, A.; Knösel, Thomas; Gruber, Elisabeth S.; Oberhuber, Georg; Bolik, Julia; Rehman, Ateequr; Sinha, Anupam; Lokau, Juliane; Arnold, Philipp; Cabron, Anne-Sophie; Zunke, Friederike; Becker‐Pauly, Christoph; Preaudet, Adele; Nguyen, Paul M.; Huynh, Jennifer; Afshar‐Sterle, Shoukat; Chand, Ashwini L.; Westermann, Jürgen; Dempsey, Peter J.; Garbers, Christoph; Schmidt-Arras, Dirk; Rosenstiel, Philip; Putoczki, Tracy L.; Ernst, Matthias; Rose–John, Stefan

doi:10.1084/jem.20171696

Cited by 65 publications

(77 citation statements)

References 84 publications

(135 reference statements)

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“…Accordingly, bazedoxifene treatment also reduced the growth of patient‐derived colon cancer organoids that harbor the APC driver, and possibly compounding additional mutations. However, given that conventional IL11 signaling and IL6 trans‐signaling both facilitate the growth of intestinal tumors (Putoczki et al , ; Schmidt et al , ), our observations do not address the relative contribution by which the bazedoxifene effect is mediated through inhibition of each of these mechanisms. Given the collective contribution of these gp130 cytokines in driving tumorigenesis, bazedoxifene may represent a potent mode for the simultaneous inhibition of conventional IL11 and IL6 trans‐signaling in tumors.…”

Section: Discussionmentioning

confidence: 81%

Repurposing the selective estrogen receptor modulator bazedoxifene to suppress gastrointestinal cancer growth

et al. 2019

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Excessive signaling through gp130, the shared receptor for the interleukin ( IL )6 family of cytokines, is a common hallmark in solid malignancies and promotes their progression. Here, we established the in vivo utility of bazedoxifene, a steroid analog clinically approved for the treatment of osteoporosis, to suppress gp130‐dependent tumor growth of the gastrointestinal epithelium. Bazedoxifene administration reduced gastric tumor burden in gp130 Y757F mice, where tumors arise exclusively through excessive gp130/ STAT 3 signaling in response to the IL 6 family cytokine IL 11. Likewise, in mouse models of sporadic colon and intestinal cancers, which arise from oncogenic mutations in the tumor suppressor gene Apc and the associated β‐catenin/canonical WNT pathway, bazedoxifene treatment reduces tumor burden. Consistent with the proposed orthogonal tumor‐promoting activity of IL 11‐dependent gp130/ STAT 3 signaling, tumors of bazedoxifene ‐treated Apc ‐mutant mice retain excessive nuclear accumulation of β‐catenin and aberrant WNT pathway activation. Likewise, bazedoxifene treatment of human colon cancer cells harboring mutant APC did not reduce aberrant canonical WNT signaling, but suppressed IL 11‐dependent STAT 3 signaling. Our findings provide compelling proof of concept to support the repurposing of bazedoxifene for the treatment of gastrointestinal cancers in which IL 11 plays a tumor‐promoting role.

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Section: Discussionmentioning

confidence: 81%

Repurposing the selective estrogen receptor modulator bazedoxifene to suppress gastrointestinal cancer growth

et al. 2019

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“…Here, we found that increased activity of meprin β on the cell surface reduced cell proliferation. Another pathway influenced by ADAM17, emerging in different tumor entities, is interleukin 6 (IL-6) and IL-6R-induced trans-signaling (Bergmann et al, 2017;Schmidt et al, 2018). Here, ADAM17 releases the IL-6R from the cell surface of one cell, and then this soluble receptor forms a signaling complex together with its cytokine and gp130 (also known as IL6ST) on another cell to induce cell survival via STAT3 phosphorylation (Schaper and Rose-John, 2015).…”

Section: Discussionmentioning

confidence: 99%

The cancer-associated meprin β variant G32R provides an additional activation site and promotes cancer cell invasion

Schäffler¹,

Li²,

Helm³

et al. 2019

Journal of Cell Science

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The extracellular metalloprotease meprin β is expressed as a homodimer and is primarily membrane bound. Meprin β can be released from the cell surface by its known sheddases ADAM10 and ADAM17. Activation of pro-meprin β at the cell surface prevents its shedding, thereby stabilizing its proteolytic activity at the plasma membrane. We show that a single amino acid exchange variant (G32R) of meprin β, identified in endometrium cancer, is more active against a peptide substrate and the IL-6 receptor than wild-type meprin β. We demonstrate that the change to an arginine residue at position 32 represents an additional activation site used by furin-like proteases in the Golgi, which consequently leads to reduced shedding by ADAM17. We investigated this meprin β G32R variant to assess cell proliferation, invasion through a collagen IV matrix and outgrowth from tumor spheroids. We found that increased meprin β G32R activity at the cell surface reduces cell proliferation, but increases cell invasion.

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“…In combination, these metagenomics markers and the standard fecal occult blood test even showed an improved sensitivity at the same level of specificity, thus improving the accuracy of diagnosis. Emerging data suggest that certain groups of bacteria might promote whereas others might protect against colon cancer ( Couturier-Maillard et al, 2013 ; Radulovic et al, 2018 ; Schmidt et al, 2018 ). Indeed, F. nucleatum seems to play a central role in the tumor microenvironment as its abundance correlates with cancer progression as well as the dysbiotic tumor microbiota composition including Bacteroides , Selenomonas , and Prevotella species.…”

Section: Microorganisms Modulate Cancer Susceptibility and Developmenmentioning

confidence: 99%

Grow With the Challenge – Microbial Effects on Epithelial Proliferation, Carcinogenesis, and Cancer Therapy

et al. 2018

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The eukaryotic host is in close contact to myriads of resident and transient microbes, which influence the crucial physiological pathways. Emerging evidence points to their role of host–microbe interactions for controlling tissue homeostasis, cell fate decisions, and regenerative capacity in epithelial barrier organs including the skin, lung, and gut. In humans and mice, it has been shown that the malignant tumors of these organs harbor an altered microbiota. Mechanistic studies have shown that the altered metabolic properties and secreted factors contribute to epithelial carcinogenesis and tumor progression. Exciting recent work points toward a crucial influence of the associated microbial communities on the response to chemotherapy and immune-check point inhibitors during cancer treatment, which suggests that the modulation of the microbiota might be a powerful tool for personalized oncology. In this article, we provide an overview of how the bacterial signals and signatures may influence epithelial homeostasis across taxa from cnidarians to vertebrates and delineate mechanisms, which might be potential targets for therapy of human diseases by either harnessing barrier integrity (infection and inflammation) or restoring uncontrolled proliferation (cancer).

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ADAM17 is required for EGF-R–induced intestinal tumors via IL-6 trans-signaling

Cited by 65 publications

References 84 publications

Repurposing the selective estrogen receptor modulator bazedoxifene to suppress gastrointestinal cancer growth

Repurposing the selective estrogen receptor modulator bazedoxifene to suppress gastrointestinal cancer growth

The cancer-associated meprin β variant G32R provides an additional activation site and promotes cancer cell invasion

Grow With the Challenge – Microbial Effects on Epithelial Proliferation, Carcinogenesis, and Cancer Therapy

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