Our scientific goal is to understand the molecular mechanisms underlying cancer progression. To this end, we study ADAMs - a family of proteolytic enzymes with important pro-tumorigenic functions.
A disintegrin and metalloproteases (ADAMS) mediate the ectodomain shedding of cell surface molecules, such as growth factors, cytokines and various receptors. The overall aim of our research is to understand fundamental properties and mechanisms of ADAMs in normal cell biology and disease – especially cancer. Using a range of biochemical and cell biology methods, murine disease models and human patient material, we investigate novel ADAM substrates and interacting molecules, and their complex regulation by intracellular signaling and trafficking pathways. Most current projects are geared towards understanding the role of ADAMs in the cross-talk between cancer cells and non-malignant cells in the tumor microenvironment.
The Kveiborg group has contributed mechanistic insight on the role of ADAMs in cancer (Fig. 1).
ADAM17-mediated EGFR activation
- We identified phosphofurin acidic cluster sorting protein (PACS)-2 as a novel regulator of ADAM17-mediated EGFR activation Dombernowsky et al. Nature Com (2015).
- We investigated EGFR-driven pathologies in PACS-2 deficient mice Dombernowsky, Swartz et al. Oncotarget (2017).
- In a large collaborative study, we identified protein phosphatase (PP)2A as a novel regulator of ADAM17-mediated EGFR activation Kruse, Gnosa, Nasa, Garvanska et al. EMBO J (2020).
- We were the first to characterize endocytic pathways regulating ADAM functions Stautz et al. Traffic 2012; Mygind et al. J Biol Chem (2018).
Cancer cell invasion
- We showed that ADAM12 exerts its pro-tumorigenic effect, at least in part, via activation of MT1-MMP Albrechtsen et al. J Cell Sci (2013).
- We defined a new mechanism whereby ADAM9 stimulates cancer cell migration by assisting β1 integrin endocytosis Mygind et al. J Cell Sci 2018.
- We identified the pro-invasive protein basigin as a novel ADAM12 substrate Albrechtsen et al. Int J Mol Sci (2019).
Cellular cross-talk in the TME
Tumor progression rely on interactions between cancer cells and stromal cells – e.g. fibroblasts and immune cells in the tumor microenvironment (TME). We hypothesize that ADAMs, expressed at the cancer cell surface, shed signaling molecules of key importance for establishing a pro-tumorigenic TME. Current projects investigate the role of selected ADAMs in TME remodeling. Using an iterative experimental platform, comprising in vitro co-cultures, in vivo models and human cancer patient material, coupled with multi-omics analyses (Fig. 2), we examine how ADAM proteases affect the TME.
Targeting ADAM functions is considered a promising strategy to halt cancer progression. However, selective ADAM inhibition has proven difficult and a better understanding of the mechanisms regulating ADAM functions is needed. Using biochemical and cell biology methods, we study how intracellular trafficking mechanisms regulate ADAM function. We believe that understanding this layer of spatial regulation will reveal new means to therapeutically control localized shedding activities.
Kruse T#, Gnosa SP#, Nasa I#, Garvanska DH#, Hein JB, Nguyen H, Samsøe-Petersen J, Lopez-Mendez B, Hertz EPT, Schwarz J, Pena HS, Nikodemus D, Kveiborg M*, Kettenbach AN, Nilsson. (2020) Mechanisms of site-specific dephosphorylation and kinase opposition imposed by PP2A regulatory subunits. EMBO J. 39:e103695, #joint first and *joint last authors
Albrechtsen R, Wewer Albrechtsen NJ, Gnosa S, Schwarz J, Dyrskjøt L, Kveiborg M. (2019) Identification of ADAM12 as a Novel Basigin Sheddase. Int J Mol Sci. 20: ijms20081957
Mygind KJ, Störiko T, Freiberg ML, Samsøe-Petersen J, Schwarz J, Andersen OM, Kveiborg M. (2018) Sorting nexin 9 (SNX9) regulates levels of the transmembrane ADAM9 at the cell surface. J Biol Chem 293:8077-8088
Mygind KJ, Schwarz J, Sahgal P, Ivaska J, Kveiborg M. (2018) Loss of ADAM9 expression impairs b1 integrin endocytosis, focal adhesion formation and cancer cell migration. J Cell Sci 131: jsc205393 (PMID 29142101)
Dombernowsky SL, Schwarz J, Samsøe-Petersen J, Albrechtsen R, Jensen KB, Thomas G, Kveiborg M. (2017) Loss of PACS-2 delays regeneration in DSS-induced colitis but does not affect the ApcMin model of colorectal cancer. Oncotarget 8:108303-108315 (PMID 29312533)
Dombernowsky SL, Samsøe-Petersen J, Petersen CH, Instrell R, Hedegaard AM, Thomas L, Atkins KM, Auclair S, Albrechtsen R, Mygind KJ, Fröhlich C, Howell M, Parker P, Thomas G, Kveiborg M. (2015) The sorting protein PACS-2 promotes ErbB signalling by regulating recycling of the metalloproteinase ADAM17. Nat Commun 6:7518 (PMID 26108729)
The Kveiborg Group collaborates closely with a number of well-renowned international and national scientists in the area of Protease Function and Regulation, and the Tumour Microenvironment.
Current Funding Agencies
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