Our research is dedicated to understanding the role and regulation of cell surface proteins in tumor progression. Specifically, we study the importance of ADAM proteases, their complex network of interaction partners and substrates, and their control by intracellular signaling and trafficking pathways.
ADAMs (A Disintegrin and Metalloproteases) are key enzymes mediating the ectodomain shedding of numerous cell surface molecules, thereby affecting many cellular processes of both physiological and pathological importance. Our overall scientific objective is to understand fundamental properties and mechanisms of ADAMs in normal cell biology and disease – especially cancer. We examine the complex interplay between ADAMs and other cell surface proteins (e.g. integrins) and how this contributes to tumor cell proliferation, invasion and survival. Our studies range from biochemical structure/function analyses to murine disease models and human tumor material. We have recently performed several screens to identify novel ADAM substrates, interaction partners and regulators. Moreover, we investigate the subcellular localization and trafficking of ADAM proteases, and the role of protein kinases, adaptor and transport proteins in their spatiotemporal control.
Novel ADAM17 regulatory pathways
The invasive phenotype of cancer cells is partly determined by changes in signaling cascades from receptor tyrosine kinases (RTKs). ADAMs, particularly ADAM17 are key enzymes in RTK signaling by ectodomain shedding of receptors and/or their respective membrane-bound ligands. We investigate intracellular signaling and sorting pathways controlling ADAM17-mediated ectodomain shedding. We have performed a human genome-wide RNA interference screen to identify novel molecular mechanisms controlling ADAM17 activity. Using both in vitro and in vivo cancer models, ongoing studies are based on the candidate regulatory pathways of ADAM17 protease function that were identified.
Intracellular trafficking of ADAMs
Intracellular trafficking and compartmentalization of ADAMs are emerging as important levels of regulation. We have shown that mechanisms involving protein kinase C (PKC) and Src kinases regulate ADAM12 subcellular localization. Our recent data demonstrate that ADAM12 is constitutively internalized through a clathrin-dependent pathway involving interaction with the adaptor protein Grb2. We are currently investigating endocytosis of other ADAM proteins (e.g. ADAM9), and the implication of intracellular kinases (PKC and Src) and adaptor proteins (Grb2, endophilins and sorting nexins) in this process. Based on these studies, we expect to determine how such spatial control mechanisms convey specificity to the apparent redundancy of ADAM proteases and ultimately, how they contribute to perturbed ADAM function in cancer.
The interplay between ADAMs and other surface proteins
ADAM activities involve dynamic interactions with other proteins at the cell surface, for example integrins. We demonstrated that ligation of ADAM12 at the cell surface induced the formation of invadopodia, actin-rich structures important for cell invasion, through pathways involving beta 3 integrin and Src kinase activity. Further studies indicated that ADAM12 enhanced the amount and activity of the key cancer protease MMP14. Ongoing studies aim to understand the interplay between ADAMs, integrins and MMP14 and how this affects tumor cell behavior.
Therapeutic targeting of ADAM12 in cancer
ADAM12 is implicated in a variety of human diseases and particularly its role in cancer has been extensively studied. ADAM12 is highly upregulated in a variety of human carcinomas and expression levels correlate with disease stage. We found that ADAM12 accelerates tumor progression in mouse models of cancer and regulates tumor cell proliferation and/or survival in vitro and in vivo. We are investigating how ADAM12 modulates tumor progression through pathways involving both protease-dependent and –independent mechanisms. We examine how ADAM12 is regulated and try to develop alternative strategies to target ADAM12 activities.
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)
2.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)
3.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)
4.Albrechtsen R, Kveiborg M, Stautz D, Vikeså J, Noer JB, Kotzsh A, Nielsen FC, Wewer U, Fröhlich C. (2013) ADAM12 redistributes and activates MMP-14, resulting in gelatin degradation, reduced apoptosis, and increased tumor growth. J Cell Sci 126:4707-20 (PMID: 24006261)
5.Stautz D, Leyme A, Grandal MV, Albrechtsen R, van Deurs B, Wewer UM, Kveiborg M. (2012) Cell-surface metalloprotease ADAM12 is internalized by a clathrin- and Grb2-dependent mechanism. Traffic 13:1532-46 (PMID: 22882974)
Members of Kveiborg group
We are always looking for highly motivated postdocs and students (Master and PhD students). For open calls, please see jobs at BRIC. Please contact Marie Kveiborg for current opportunities.