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Article ; Online: Transmembrane transporter proteins: Capturing transport in motion.

Loland, Claus J / Wellendorph, Petrine / Pedersen, Stine F / Gether, Ulrik

Basic & clinical pharmacology & toxicology

2023 Volume 134, Issue 2, Page(s) 203–205

MeSH term(s)	Membrane Transport Proteins/metabolism ; Membrane Proteins ; Carrier Proteins ; Biological Transport
Chemical Substances	Membrane Transport Proteins ; Membrane Proteins ; Carrier Proteins
Language	English
Publishing date	2023-11-23
Publishing country	England
Document type	Editorial
ZDB-ID	2134679-3
ISSN	1742-7843 ; 1742-7835
ISSN (online)	1742-7843
ISSN	1742-7835
DOI	10.1111/bcpt.13960
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Article ; Online: Aquaporin water channels affect the response of conventional anticancer therapies of 3D grown breast cancer cells.

Edamana, Sarannya / Pedersen, Stine F / Nejsum, Lene N

Biochemical and biophysical research communications

2022 Volume 639, Page(s) 126–133

Abstract: Aquaporin (AQP) water channels facilitate water transport across cellular membranes and are essential in regulation of body water balance. Moreover, several AQPs are overexpressed or ectopically expressed in breast cancer. Interestingly, several in vitro ...

Abstract	Aquaporin (AQP) water channels facilitate water transport across cellular membranes and are essential in regulation of body water balance. Moreover, several AQPs are overexpressed or ectopically expressed in breast cancer. Interestingly, several in vitro studies have suggested that AQPs can affect the response to conventional anticancer chemotherapies. Therefore, we took a systematic approach to test how AQP1, AQP3 and AQP5, which are often over-/ectopically expressed in breast cancer, affect total viability of 3-dimensional (3D) breast cancer cell spheroids when treated with the conventional anticancer chemotherapies Cisplatin, 5-Fluorouracil (5-FU) and Doxorubicin, a Combination of the three drugs as well as the Combination plus the Ras inhibitor Salirasib. Total viability of spheroids overexpressing AQP1 were decreased by all treatments except for 5-FU, which increased total viability by 20% compared to DMSO treated controls. All treatments reduced viability of spheroids overexpressing AQP3. In contrast, only Doxorubicin, Combination and Combination + Salirasib reduced total viability of spheroids overexpressing AQP5. Thus, this study supports a significant role of AQPs in the response to conventional chemotherapies. Evaluating the role of individual proteins that contribute to resistance to chemotherapies is essential in advancing personalized medicine in breast carcinomas.
MeSH term(s)	Humans ; Female ; Breast Neoplasms/drug therapy ; Aquaporins/metabolism ; Fluorouracil/pharmacology ; Doxorubicin/pharmacology ; Aquaporin 1/genetics ; Aquaporin 1/metabolism ; Aquaporin 5/metabolism ; Aquaporin 3/genetics ; Aquaporin 3/metabolism ; Aquaporin 4 ; Aquaporin 2
Chemical Substances	farnesylthiosalicylic acid ; Aquaporins ; Fluorouracil (U3P01618RT) ; Doxorubicin (80168379AG) ; Aquaporin 1 (146410-94-8) ; Aquaporin 5 ; Aquaporin 3 (158801-98-0) ; Aquaporin 4 ; Aquaporin 2
Language	English
Publishing date	2022-11-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2022.11.096
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Article ; Online: The Interplay between Dysregulated Ion Transport and Mitochondrial Architecture as a Dangerous Liaison in Cancer.

Pedersen, Stine F / Flinck, Mette / Pardo, Luis A

International journal of molecular sciences

2021 Volume 22, Issue 10

Abstract: Transport of ions and nutrients is a core mitochondrial function, without which there would be no mitochondrial metabolism and ATP production. Both ion homeostasis and mitochondrial phenotype undergo pervasive changes during cancer development, and both ... ...

Abstract	Transport of ions and nutrients is a core mitochondrial function, without which there would be no mitochondrial metabolism and ATP production. Both ion homeostasis and mitochondrial phenotype undergo pervasive changes during cancer development, and both play key roles in driving the malignancy. However, the link between these events has been largely ignored. This review comprehensively summarizes and critically discusses the role of the reciprocal relationship between ion transport and mitochondria in crucial cellular functions, including metabolism, signaling, and cell fate decisions. We focus on Ca
MeSH term(s)	Calcium/metabolism ; Cell Movement ; Cell Proliferation ; Homeostasis ; Humans ; Ion Channels/metabolism ; Ion Transport ; Mitochondria/metabolism ; Neoplasms/metabolism ; Neoplasms/pathology ; Neoplastic Stem Cells/metabolism ; Potassium/metabolism ; Protons ; Tumor Microenvironment
Chemical Substances	Ion Channels ; Protons ; Potassium (RWP5GA015D) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2021-05-14
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22105209
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Article ; Online: The Acidic Tumor Microenvironment as a Driver of Cancer.

Boedtkjer, Ebbe / Pedersen, Stine F

Annual review of physiology

2019 Volume 82, Page(s) 103–126

Abstract: Acidic metabolic waste products accumulate in the tumor microenvironment because of high metabolic activity and insufficient perfusion. In tumors, the acidity of the interstitial space and the relatively well-maintained intracellular pH influence cancer ... ...

Abstract	Acidic metabolic waste products accumulate in the tumor microenvironment because of high metabolic activity and insufficient perfusion. In tumors, the acidity of the interstitial space and the relatively well-maintained intracellular pH influence cancer and stromal cell function, their mutual interplay, and their interactions with the extracellular matrix. Tumor pH is spatially and temporally heterogeneous, and the fitness advantage of cancer cells adapted to extracellular acidity is likely particularly evident when they encounter less acidic tumor regions, for instance, during invasion. Through complex effects on genetic stability, epigenetics, cellular metabolism, proliferation, and survival, the compartmentalized pH microenvironment favors cancer development. Cellular selection exacerbates the malignant phenotype, which is further enhanced by acid-induced cell motility, extracellular matrix degradation, attenuated immune responses, and modified cellular and intercellular signaling. In this review, we discuss how the acidity of the tumor microenvironment influences each stage in cancer development, from dysplasia to full-blown metastatic disease.
MeSH term(s)	Acids/metabolism ; Animals ; Humans ; Hydrogen-Ion Concentration ; Neoplasm Metastasis ; Neoplasms/metabolism ; Neoplasms/pathology ; Signal Transduction ; Tumor Microenvironment
Chemical Substances	Acids
Language	English
Publishing date	2019-11-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	207933-1
ISSN	1545-1585 ; 0066-4278
ISSN (online)	1545-1585
ISSN	0066-4278
DOI	10.1146/annurev-physiol-021119-034627
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Article ; Online: MCT4 and CD147 colocalize with MMP14 in invadopodia and support matrix degradation and invasion by breast cancer cells.

Meng, Signe / Sørensen, Ester E / Ponniah, Muthulakshmi / Thorlacius-Ussing, Jeppe / Crouigneau, Roxane / Larsen, Tanja / Borre, Magnus T / Willumsen, Nicholas / Flinck, Mette / Pedersen, Stine F

Journal of cell science

2024 Volume 137, Issue 8

Abstract: Expression levels of the lactate-H+ cotransporter MCT4 (also known as SLC16A3) and its chaperone CD147 (also known as basigin) are upregulated in breast cancers, correlating with decreased patient survival. Here, we test the hypothesis that MCT4 and ... ...

Abstract	Expression levels of the lactate-H+ cotransporter MCT4 (also known as SLC16A3) and its chaperone CD147 (also known as basigin) are upregulated in breast cancers, correlating with decreased patient survival. Here, we test the hypothesis that MCT4 and CD147 favor breast cancer invasion through interdependent effects on extracellular matrix (ECM) degradation. MCT4 and CD147 expression and membrane localization were found to be strongly reciprocally interdependent in MDA-MB-231 breast cancer cells. Overexpression of MCT4 and/or CD147 increased, and their knockdown decreased, migration, invasion and the degradation of fluorescently labeled gelatin. Overexpression of both proteins led to increases in gelatin degradation and appearance of the matrix metalloproteinase (MMP)-generated collagen-I cleavage product reC1M, and these increases were greater than those observed upon overexpression of each protein alone, suggesting a concerted role in ECM degradation. MCT4 and CD147 colocalized with invadopodia markers at the plasma membrane. They also colocalized with MMP14 and the lysosomal marker LAMP1, as well as partially with the autophagosome marker LC3, in F-actin-decorated intracellular vesicles. We conclude that MCT4 and CD147 reciprocally regulate each other and interdependently support migration and invasiveness of MDA-MB-231 breast cancer cells. Mechanistically, this involves MCT4-CD147-dependent stimulation of ECM degradation and specifically of MMP-mediated collagen-I degradation. We suggest that the MCT4-CD147 complex is co-delivered to invadopodia with MMP14.
MeSH term(s)	Humans ; Basigin/metabolism ; Basigin/genetics ; Monocarboxylic Acid Transporters/metabolism ; Monocarboxylic Acid Transporters/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Breast Neoplasms/genetics ; Matrix Metalloproteinase 14/metabolism ; Matrix Metalloproteinase 14/genetics ; Podosomes/metabolism ; Female ; Cell Line, Tumor ; Neoplasm Invasiveness ; Extracellular Matrix/metabolism ; Cell Movement ; Muscle Proteins/metabolism ; Muscle Proteins/genetics ; Lysosomal Membrane Proteins/metabolism ; Lysosomal Membrane Proteins/genetics ; Gelatin/metabolism ; Microtubule-Associated Proteins/metabolism ; Microtubule-Associated Proteins/genetics ; Cell Membrane/metabolism ; Lysosomal-Associated Membrane Protein 1
Chemical Substances	Basigin (136894-56-9) ; Monocarboxylic Acid Transporters ; Matrix Metalloproteinase 14 (EC 3.4.24.80) ; SLC16A4 protein, human ; BSG protein, human ; MMP14 protein, human (EC 3.4.24.80) ; Muscle Proteins ; LAMP1 protein, human ; Lysosomal Membrane Proteins ; Gelatin (9000-70-8) ; Microtubule-Associated Proteins ; Lysosomal-Associated Membrane Protein 1
Language	English
Publishing date	2024-04-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
DOI	10.1242/jcs.261608
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Article ; Online: Spatially resolved analysis of microenvironmental gradient impact on cancer cell phenotypes.

Auxillos, Jamie / Crouigneau, Roxane / Li, Yan-Fang / Dai, Yifan / Stigliani, Arnaud / Tavernaro, Isabella / Resch-Genger, Ute / Sandelin, Albin / Marie, Rodolphe / Pedersen, Stine F

Science advances

2024 Volume 10, Issue 18, Page(s) eadn3448

Abstract: Despite the physiological and pathophysiological significance of microenvironmental gradients, e.g., for diseases such as cancer, tools for generating such gradients and analyzing their impact are lacking. Here, we present an integrated microfluidic- ... ...

Abstract	Despite the physiological and pathophysiological significance of microenvironmental gradients, e.g., for diseases such as cancer, tools for generating such gradients and analyzing their impact are lacking. Here, we present an integrated microfluidic-based workflow that mimics extracellular pH gradients characteristic of solid tumors while enabling high-resolution live imaging of, e.g., cell motility and chemotaxis, and preserving the capacity to capture the spatial transcriptome. Our microfluidic device generates a pH gradient that can be rapidly controlled to mimic spatiotemporal microenvironmental changes over cancer cells embedded in a 3D matrix. The device can be reopened allowing immunofluorescence analysis of selected phenotypes, as well as the transfer of cells and matrix to a Visium slide for spatially resolved analysis of transcriptional changes across the pH gradient. This workflow is easily adaptable to other gradients and multiple cell types and can therefore prove invaluable for integrated analysis of roles of microenvironmental gradients in biology.
MeSH term(s)	Humans ; Tumor Microenvironment ; Phenotype ; Neoplasms/pathology ; Neoplasms/metabolism ; Neoplasms/genetics ; Cell Line, Tumor ; Cell Movement ; Hydrogen-Ion Concentration ; Chemotaxis ; Microfluidic Analytical Techniques
Language	English
Publishing date	2024-05-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.adn3448
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Article ; Online: Why Warburg Works: Lactate Controls Immune Evasion through GPR81.

Lundø, Kathrine / Trauelsen, Mette / Pedersen, Stine F / Schwartz, Thue W

Cell metabolism

2020 Volume 31, Issue 4, Page(s) 666–668

Abstract: Lactate accumulation in tumors-a hallmark of the Warburg effect-has recently been shown to regulate cancer cell metabolism and survival through autocrine activation of GPR81. Now, Brown et al. (2020) demonstrate that lactate surprisingly also controls ... ...

Abstract	Lactate accumulation in tumors-a hallmark of the Warburg effect-has recently been shown to regulate cancer cell metabolism and survival through autocrine activation of GPR81. Now, Brown et al. (2020) demonstrate that lactate surprisingly also controls immune evasion through paracrine activation of GPR81 on stromal dendritic cells.
MeSH term(s)	Antigen-Presenting Cells ; Breast Neoplasms ; Humans ; Immune Evasion ; Lactic Acid ; Receptors, G-Protein-Coupled ; Tumor Microenvironment
Chemical Substances	Receptors, G-Protein-Coupled ; Lactic Acid (33X04XA5AT)
Language	English
Publishing date	2020-04-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	2176834-1
ISSN	1932-7420 ; 1550-4131
ISSN (online)	1932-7420
ISSN	1550-4131
DOI	10.1016/j.cmet.2020.03.001
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Article ; Online: Assessing Cell Viability and Death in 3D Spheroid Cultures of Cancer Cells.

Rolver, Michala G / Elingaard-Larsen, Line O / Pedersen, Stine F

Journal of visualized experiments : JoVE

2019 , Issue 148

Abstract: Three-dimensional spheroids of cancer cells are important tools for both cancer drug screens and for gaining mechanistic insight into cancer cell biology. The power of this preparation lies in its ability to mimic many aspects of the in vivo conditions ... ...

Abstract	Three-dimensional spheroids of cancer cells are important tools for both cancer drug screens and for gaining mechanistic insight into cancer cell biology. The power of this preparation lies in its ability to mimic many aspects of the in vivo conditions of tumors while being fast, cheap, and versatile enough to allow relatively high-throughput screening. The spheroid culture conditions can recapitulate the physico-chemical gradients in a tumor, including the increasing extracellular acidity, increased lactate, and decreasing glucose and oxygen availability, from the spheroid periphery to its core. Also, the mechanical properties and cell-cell interactions of in vivo tumors are in part mimicked by this model. The specific properties and consequently the optimal growth conditions, of 3D spheroids, differ widely between different types of cancer cells. Furthermore, the assessment of cell viability and death in 3D spheroids requires methods that differ in part from those employed for 2D cultures. Here we describe several protocols for preparing 3D spheroids of cancer cells, and for using such cultures to assess cell viability and death in the context of evaluating the efficacy of anticancer drugs.
MeSH term(s)	Cell Culture Techniques/methods ; Cell Line, Tumor ; Cell Survival/physiology ; Humans ; Neoplasms/pathology ; Spheroids, Cellular/physiology
Language	English
Publishing date	2019-06-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Video-Audio Media
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/59714
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Article ; Online: Pyrazine ring-based Na

Rolver, Michala G / Elingaard-Larsen, Line O / Andersen, Anne P / Counillon, Laurent / Pedersen, Stine F

Scientific reports

2020 Volume 10, Issue 1, Page(s) 5800

Abstract: ... The ... ...

Abstract	The Na
MeSH term(s)	Amiloride/pharmacology ; Antineoplastic Agents/pharmacology ; Apoptosis ; Autophagy ; Cell Proliferation ; Endoplasmic Reticulum Stress ; Guanidines/pharmacology ; Humans ; MCF-7 Cells ; Neoplasms/metabolism ; Sodium-Hydrogen Exchanger 1/genetics ; Sodium-Hydrogen Exchanger 1/metabolism ; Spheroids, Cellular/drug effects ; Spheroids, Cellular/metabolism ; Sulfones/pharmacology
Chemical Substances	Antineoplastic Agents ; Guanidines ; SLC9A1 protein, human ; Sodium-Hydrogen Exchanger 1 ; Sulfones ; Amiloride (7DZO8EB0Z3) ; cariporide (7E3392891K) ; eniporide (7IGF9182QU)
Language	English
Publishing date	2020-04-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-62430-z
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Article: How Reciprocal Interactions Between the Tumor Microenvironment and Ion Transport Proteins Drive Cancer Progression.

Elingaard-Larsen, Line O / Rolver, Michala G / Sørensen, Ester E / Pedersen, Stine F

Reviews of physiology, biochemistry and pharmacology

2020 Volume 182, Page(s) 1–38

Abstract: Solid tumors comprise two major components: the cancer cells and the tumor stroma. The stroma is a mixture of cellular and acellular components including fibroblasts, mesenchymal and cancer stem cells, endothelial cells, immune cells, extracellular ... ...

Abstract	Solid tumors comprise two major components: the cancer cells and the tumor stroma. The stroma is a mixture of cellular and acellular components including fibroblasts, mesenchymal and cancer stem cells, endothelial cells, immune cells, extracellular matrix, and tumor interstitial fluid. The insufficient tumor perfusion and the highly proliferative state and dysregulated metabolism of the cancer cells collectively create a physicochemical microenvironment characterized by altered nutrient concentrations and varying degrees of hypoxia and acidosis. Furthermore, both cancer and stromal cells secrete numerous growth factors, cytokines, and extracellular matrix proteins which further shape the tumor microenvironment (TME), favoring cancer progression.Transport proteins expressed by cancer and stromal cells localize at the interface between the cells and the TME and are in a reciprocal relationship with it, as both sensors and modulators of TME properties. It has been amply demonstrated how acid-base and nutrient transporters of cancer cells enable their growth, presumably by contributing both to the extracellular acidosis and the exchange of metabolic substrates and waste products between cells and TME. However, the TME also impacts other transport proteins important for cancer progression, such as multidrug resistance proteins. In this review, we summarize current knowledge of the cellular and acellular components of solid tumors and their interrelationship with key ion transport proteins. We focus in particular on acid-base transport proteins with known or proposed roles in cancer development, and we discuss their relevance for novel therapeutic strategies.
MeSH term(s)	Carrier Proteins/therapeutic use ; Endothelial Cells ; Humans ; Neoplasms/drug therapy ; Neoplastic Processes ; Tumor Microenvironment
Chemical Substances	Carrier Proteins
Language	English
Publishing date	2020-08-02
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	125106-5
ISSN	1617-5786 ; 0303-4240
ISSN (online)	1617-5786
ISSN	0303-4240
DOI	10.1007/112_2020_23
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