ADAM8 as a drug target in pancreatic cancer
Uwe Schlomann,Garrit Koller,Catharina Conrad,Taheera Ferdous,Panagiota Golfi,Adolfo Molejon Garcia,Sabrina Höfling,Madeline Parsons,Patricia Costa,Robin Soper,Maud Bossard,Thorsten Hagemann,Rozita Roshani,Norbert Sewald,Randal R. Ketchem,Marcia L. Moss,Fred H. Rasmussen,Miles A. Miller,Douglas A. Lauffenburger,David A. Tuveson,Christopher Nimsky,Joerg W. Bartsch +21 more
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TLDR
The data integrate ADAM8 in pancreatic cancer signalling and validateADAM8 as a target for PDAC therapy are validated.Abstract:
Pancreatic ductal adenocarcinoma (PDAC) has a grim prognosis with <5% survivors after 5 years. High expression levels of ADAM8, a metalloprotease disintegrin, are correlated with poor clinical outcome. We show that ADAM8 expression is associated with increased migration and invasiveness of PDAC cells caused by activation of ERK1/2 and higher MMP activities. For biological function, ADAM8 requires multimerization and associates with β1 integrin on the cell surface. A peptidomimetic ADAM8 inhibitor, BK-1361, designed by structural modelling of the disintegrin domain, prevents ADAM8 multimerization. In PDAC cells, BK-1361 affects ADAM8 function leading to reduced invasiveness, and less ERK1/2 and MMP activation. BK-1361 application in mice decreased tumour burden and metastasis of implanted pancreatic tumour cells and provides improved metrics of clinical symptoms and survival in a Kras(G12D)-driven mouse model of PDAC. Thus, our data integrate ADAM8 in pancreatic cancer signalling and validate ADAM8 as a target for PDAC therapy.read more
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Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions.
Orianne Olivares,Jared R. Mayers,Victoire Gouirand,Margaret E. Torrence,Tristan Gicquel,Laurence Borge,Sophie Lac,Julie Roques,Marie-Noëlle Lavaut,Patrice Berthezene,Marion Rubis,Véronique Secq,Stéphane Garcia,Vincent Moutardier,Dominique Lombardo,Juan L. Iovanna,Richard Tomasini,Fabienne Guillaumond,Matthew G. Vander Heiden,Matthew G. Vander Heiden,Sophie Vasseur +20 more
TL;DR: It is demonstrated that collagen serves as a proline reservoir for PDAC cells to use as a nutrient source when other fuels are limited and that proline oxidase (PRODH1) is required forPDAC cell proliferation in vitro and in vivo.
Journal ArticleDOI
Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments
Stefan F. Lichtenthaler,Stefan F. Lichtenthaler,Marius K. Lemberg,Regina Fluhrer,Regina Fluhrer +4 more
TL;DR: It is expected that shedding is not a rare exception, but rather the rule for many membrane proteins, and that many more interesting shedding functions await discovery.
Journal ArticleDOI
YTH domain family 2 orchestrates epithelial-mesenchymal transition/proliferation dichotomy in pancreatic cancer cells.
Jixiang Chen,Yaocheng Sun,Xiao Xu,Dawei Wang,Junbo He,Hailang Zhou,Ying Lu,Jian Zeng,Fengyi Du,Aihua Gong,Min Xu +10 more
TL;DR: It is found that YTHDF2 expression is up-regulated in pancreatic cancer tissues compared with normal tissues at both mRNA and protein levels, and is higher in clinical patients with later stages of pancreatic cancers, indicating that Y THDF2 possesses potential clinical significance for diagnosis and prognosis of pancreating cancers.
Journal ArticleDOI
Shedding of Endogenous Interleukin-6 Receptor (IL-6R) Is Governed by A Disintegrin and Metalloproteinase (ADAM) Proteases while a Full-length IL-6R Isoform Localizes to Circulating Microvesicles.
Neele Schumacher,Dörte Meyer,Andre Mauermann,Jan von der Heyde,Janina Wolf,Jeanette Schwarz,Katharina Knittler,Gillian Murphy,Matthias Michalek,Christoph Garbers,Jörg W. Bartsch,Songbo Guo,Beate Schacher,Peter Eickholz,Athena Chalaris,Stefan Rose-John,Björn Rabe +16 more
TL;DR: Microvesicle release represents a novel mode of soluble IL-6 receptor generation with potential clinical implications and is established as a novel mechanism for sIL-6R generation by establishing full-length IL- 6R on circulating microvesicles.
Journal ArticleDOI
β1 Integrins as Therapeutic Targets to Disrupt Hallmarks of Cancer.
Anne-Florence Blandin,Guillaume Renner,Maxime Lehmann,Isabelle Lelong-Rebel,Sophie Martin,Monique Dontenwill +5 more
TL;DR: Current knowledge about integrin implications in those different hallmarks focusing primarily on β1 integrins is summarized, highlighting the importance of knowing these implications in the context of cancer hallmarks.
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