The NHE1 group
We study cellular acid-base homeostasis and associated signaling in normal physiology, cancer, and metabolic disease. Our specific interests are how pH is regulated in each cellular compartment, how it is sensed by cells, and how it in turn regulates cellular functions – as well as structure-function and regulatory interactions of pH regulatory transport proteins.
The key research interest of the NHE1 group is how acid-base transporters are regulated and how their function and dysfunction impact human health. In terms of specific transporters, our primary focus is SLC9A family Na+/H+ exchangers, in particular NHE1. Our expertise is the molecular- and cell biology of acid-base transport, and at a collaborative level we employ biophysical approaches, genetics and bioinformatics, and animal studies to understand the roles of NHE1 and other acid/base transporters, in particular in breast and pancreatic cancer. In the past years, we have provided important insights into how these transporters are regulated in cancer and contribute to its progression and metabolism. This includes the discovery that NHE1 acts as a regulatory scaffold for ERK kinases (Hendus-Altenburger et al, BMC Biology, 2016), and major roles of NHE1 and other acid base transporters in breast tumor growth (Andersen et al Mol Cancer 2016, Andersen et al Int J Cancer 2018). Our recent work, demonstrating the role of NHE1 in prolactin signaling (Pedraz-Cuesta et al Mol Endo, 2016), the strong upregulation of acid-base transporters in differentiating adipocytes (Petersen et al Sci Rep, 2017), and the widespread importance of lactate signaling in cancer development (Lundoe et al 2020 Cell Metab) has turned our interests to also include metabolic regulation in health and disease, as always with a focus on the role of acid-base homeostasis.
The bulk of our current projects are devoted to understanding how the acidic tumor microenvironment regulates cancer progression. This includes the roles of acid-base homeostasis in epithelial cancer development, which we study using stem cell based organoids from transgenic pancreas cancer mouse models as well as in human cancer cells; the involvement of specific acid-base transporters (NBCn1, MCTs) in shaping cancer cell phenotype; and the mechanisms through which cytosolic, organellar, and extracellular pH regulate cellular signaling and how this is altered in cancer cells. In this context we have also recently embarked on a collaborative project with the aim of setting up microfluidics-based systems to precisely control pH and oxygen gradients in time and space and study their impact on cancer cell behavior. Other ongoing and highly collaborative projects (see Collaborators) include a study addressing the role of NHE1 in non-alcoholic steatohepatitis (NASH), in which we are currently generating the first liver-specific NHE1 knockout mice; and a study addressing the mechanisms through which point mutations in the endosome-specific, X chromosome-expressed NHE isoform NHE6 cause devastating neurodegenerative disease in boys.
We have ongoing collaborations with several groups both in Denmark and abroad, including:
Prof. Albin Sandelin, BIO
Prof. Henriette Pilegaard, BIO
Prof. Birthe Kragelund, BIO
Prof. Thue Schwartz, Novo Nordisk Center for Basic Metabolism, UCPH Faculty of Health
Dr. Kenji Maeda and Dr. Bin Liu, Danish Cancer Society Research Center
Dr. Rodolphe Marie, Technical University of Denmark
Prof. Dr. Luis A. Pardo, Max Planck Institute for Experimental Medicine, Göttingen, DE
Dr. Eric Morrow, Brown University, Rhode Island, USA
Dr. Dario Longo, University of Torino, Italy
And last but not least, the pHIoniC ITN: https://www.medizin.uni-muenster.de/phionic/home.html
2020
Rolver MG, O. Elingaard-Larsen L, Counillon L, Pedersen SF. 2020. Pyrazine ring-based Na+/H+ exchanger (NHE) inhibitors potently inhibit cancer cell growth in 3D culture, independent of NHE1. Sci Rep 10(1):5800. PMID: 32242030
Cholak E, Bugge K, Khondker A, Gauger K, Pedraz-Cuesta E, Enghave Pedersen M, Bucciarelli S, Vestergaard B, Pedersen SF, Rheinstädter M, Langkilde AE, Kragelund BB. Avidity within the N-terminal anchor drives α-synuclein membrane interaction and insertion. FASEB J. 2020 Jun;34(6):7462-7482. PMID: 32277854
Flinck M, Hagelund SE, Gorbatenko A, Severin M, Pedraz-Cuesta E, Novak I, Stock CM, Pedersen SF. The Vacuolar H+ ATPase α3 Subunit Negatively Regulates Migration and Invasion of Human Pancreatic Ductal Adenocarcinoma Cells. Cells. 2020;9(2):465. PMID: 32085585
Bagdonaite I, Pallesen I, Ye Z, Vakhrushev SY, Marinova I, Nielsen M, Kramer S, Pedersen SF, Joshi HJ, Bennett EP, Dabelsteen S, Wandall H. O-glycan initiation directs distinct biological pathways and controls epithelial differentiation. EMBO Reports 2020;21(6):e48885. PMID: 32329196
Yao J, Czaplinska D, Ialchina R, Schnipper J, Liu B, Sandelin A*, Pedersen SF*. Cancer Cell Acid Adaptation Gene Expression Response Is Correlated to Tumor-Specific Tissue Expression Profiles and Patient Survival. Cancers (Basel). 2020;12(8):2183. PMID: 32764426 (*co-corresponding)
Malinda RR, Zeeberg K, Sharku PC, Ludwig MQ, Pedersen LB, Christensen ST, Pedersen SF. TGFβ Signaling Increases Net Acid Extrusion, Proliferation and Invasion in Panc-1 Pancreatic Cancer Cells: SMAD4 Dependence and Link to Merlin/NF2 Signaling. Front Oncol. 2020;10:687. eCollection 2020. PMID: 32457840
Hendus-Altenburger R, Vogensen J, Pedersen ES, Luchini A, Araya-Secchi R, Bendsoe AH, Prasad NS, Prestel A, Cardenas M, Pedraz-Cuesta E, Arleth L, Pedersen SF, Kragelund BB. The intracellular lipid-binding domain of human Na+/H+ exchanger 1 forms a lipid-protein co-structure essential for activity. Commun Biol. 2020;3(1):731. doi: 10.1038/s42003-020-01455-6. PMID: 33273619; PMCID: PMC7713384
Lundø K, Trauelsen M, Pedersen SF*, Schwartz TW*. Why Warburg works: Lactate controls immune evasion through GPR81. Cell Metabolism 2020, ;31(4):666-668, PMID: 32268113
Elingaard-Larsen L, Rolver MG, Sørensen EE, Pedersen SF. How reciprocal interactions between the tumor microenvironment and ion transport proteins drive cancer progression. Rev Physiol Biochem Pharmacol. 2020 Aug 1. doi: 10.1007/112_2020_23. Online ahead of print. PMID: 32737753
Rolver MG, Pedersen SF. Putting Warburg to work: how imaging of tumour acidosis could help predict metastatic potential in breast cancer. Br J Cancer. 2020. doi: 10.1038/s41416-020-01171-2. Epub ahead of print. PMID: 33257840
Boedtkjer E and Pedersen SF. 2020. The acidic tumor microenvironment as a driver of cancer. Annual Rev Physiol 82:103-126. PMID: 31730395
2019
Jensen HH, Pedersen GA, Morgen JJ, Parsons M, Pedersen SF, Nejsum LN. The Na+/H+ exchanger NHE1 localizes as clusters to cryptic lamellipodia and accelerates collective epithelial cell migration. J Physiol. 2019, 597(3):849-867. PMID: 30471113
Gorbatenko A, Søkilde R, Sorensen EE, Newie I, Persson H, Morancho B, Arribas J, Litman T, Rovira C, Pedersen SF. 2019. HER2 and p95HER2 differentially regulate miRNA expression in MCF-7 breast cancer cells and downregulate MYB proteins through miR-221/222 and miR-503. Sci Rep. 2019, 9(1):3352. PMID: 30833639
Bialik JF, Ding M, Speight P, Dan Q, Miranda MZ, Di Ciano-Oliveira C, Kofler MM, Rotstein OD, Pedersen SF, Szászi K, Kapus A. Profibrotic epithelial phenotype: a central role for MRTF and TAZ. Sci Rep. 2019, 9(1):4323. PMID: 30867502
Rolver MG, Elingaard-Larsen LO, Pedersen SF. Assessing Cell Viability and Death in 3D Spheroid Cultures of Cancer Cells. J Vis Exp 2019, 148. PMID: 31259899
Hendus-Altenburger R, Wang X, Sjøgaard-Frich L, Pedraz-Cuesta E, Sheftic SR, Bendsøe AH, Page R, Kragelund BB, Pedersen SF, Peti W. 2019. Molecular basis for the binding and selective dephosphorylation of Na+/H+ exchanger 1 by calcineurin. Nat Comm 10(1):3489. PMID: 31375679
Tornabene E, Helms HCC, Pedersen SF, Brodin B. 2019. Effects of oxygen-glucose deprivation (OGD) on barrier properties and mRNA transcript levels of selected marker proteins in brain endothelial cells/astrocyte co-cultures. PLoS One;14(8):e0221103. eCollection 2019. PMID: 31425564
Pedersen SF and Counillon L. 2019. The SLC9A-C mammalian Na+/H+ exchanger family: Molecules, mechanisms, and physiology. Physiol Rev 99 (4), 2015-2113, PMID: 31507243
Czaplinska D, O. Elingaard-Larsen L, Rolver MG, Severin M, Pedersen SF. 2019. 3D multicellular models to study the regulation and roles of acid-base transporters in breast cancer. Biochem. Soc. Trans. 47 (6), 1689-1700, PMID: 31803922
2018
Andersen AP, Samsoe-Petersen J, Oernboe EK, Boedtkjer E, Moreira JMA, Kveiborg K, Pedersen SF. The net acid extruders NHE1, NBCn1 and MCT4 promote mammary tumor growth through distinct but overlapping mechanisms. Int J Cancer 2018 142(12):2529-2542. PMID: 29363134
Olesen CW, Vogensen J, Pedersen IS, Stemann JHV, Schröder JM, Christensen DP, Pedersen SF. Trafficking, localization and degradation of the Na+,HCO3– cotransporter NBCn1 in kidney and breast epithelial cells. Sci Rep 2018, 8(1):7435. PMID: 29743600
Flinck M, Kramer SH, Schnipper J, Andersen AP, Pedersen SF. The acid-base transport proteins NHE1 and NBCn1 regulate cell cycle progression in human breast cancer cells. Cell Cycle 2018, 17(9):1056-1067. PMID: 29895196
Lee S, Axelsen TV, Jessen N, Pedersen SF, Vahl P, Boedtkjer E. Na+,HCO3–-cotransporter NBCn1 (Slc4a7) accelerates ErbB2-induced breast cancer development and tumor growth in mice. Oncogene, 2018, 37(41):5569-5584. PMID: 29907770
Flinck M, Kramer SH, Pedersen SF. 2018. Roles of pH in control of proliferation. Acta Physiol (Oxf), 223(3):e13068. PMID:29575508
We contribute to the following courses in the Department of Biology:
General Cell Biology (Almen Cellebiologi)
Signal Transduction (Signaltransduktion)
Advanced Cell Biology
Developmental Biology
Cellular and Integrative Biology
Cellular Signaling in Health and Disease
The Carlsberg Foundation
The Danish Cancer Society
H2020-MSCA-ITN-2018 813834
NNF Endocrinology Project Grant
NNF Exploratory Synergy Grant
Independent Research Fund Denmark – Medical Sciences
Independent Research Fund Denmark – Natural Sciences
Lectures
UCPH Forward: Lectures on motivation and role models in research (2019, 2020)
TALENT.DK: Seminar 2020 (https://www.talent-dk.dk/viden-arkiv/materiale-fra-seminarer/2020-seminar/)
Podcast
Science Stories (https://den2radio.dk/udsendelser/science-stories-luca/ and on Spotify/iTunes)
Book
“Fortællinger fra Grundforskningens Grænseland”, published 2020 by Royal Danish Academy of Science and Letters and the Danish National Research Foundation (https://dg.dk/en/new-book-on-basic-research-from-the-danish-national-research-foundation/).
Researchers
| Name | Title | Phone | |
|---|---|---|---|
| Dominika Czaplinska | Postdoc | +4535324117 | |
| Lise Margrethe Sjøgaard-Frich | PhD Fellow | +4535324904 | |
| Mette Flinck | Academic Research Staff | +4535337994 | |
| Michala Gylling Rolver | PhD Fellow | +4535336565 | |
| Muthulakshmi Ponniah | Research Assistant | +4535334589 | |
| Renata Ialchina | PhD Fellow | +4535332915 | |
| Roxane Naima Pauline Crouigneau | Postdoc | +4535334016 | |
| Stine Helene Falsig Pedersen | Professor | +4535321546 |
Other members
| Name | Title | |
|---|---|---|
| Marc Severin | PhD student | |
| Emil Tranchant | Master student | |
| Emma Probst | Master student | |
| Louise Spøhr | Master student | |
| Magnus Thane Borre | Master student | |
| Signe Meng | Master student | |
| Xiaoming Chen | Master student |
Contact
Professor
Stine Helene Falsig Pedersen
Cell Biology and Physiology
Universitetsparken 13
DK-2100 Copenhagen Ø, Denmark
sfpedersen@bio.ku.dk
Phone: +45 35 32 15 46
Mobile: +45 20 99 15 55
ORCID: 0000-0002-3044-7714