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Article: Dynamic Microtubule Arrays in Leukocytes and Their Role in Cell Migration and Immune Synapse Formation.

Kopf, Aglaja / Kiermaier, Eva

Frontiers in cell and developmental biology

2021 Volume 9, Page(s) 635511

Abstract: The organization of microtubule arrays in immune cells is critically important for a properly operating immune system. Leukocytes are white blood cells of hematopoietic origin, which exert effector functions of innate and adaptive immune responses. ... ...

Abstract	The organization of microtubule arrays in immune cells is critically important for a properly operating immune system. Leukocytes are white blood cells of hematopoietic origin, which exert effector functions of innate and adaptive immune responses. During these processes the microtubule cytoskeleton plays a crucial role for establishing cell polarization and directed migration, targeted secretion of vesicles for T cell activation and cellular cytotoxicity as well as the maintenance of cell integrity. Considering this large spectrum of distinct effector functions, leukocytes require flexible microtubule arrays, which timely and spatially reorganize allowing the cells to accommodate their specific tasks. In contrast to other specialized cell types, which typically nucleate microtubule filaments from non-centrosomal microtubule organizing centers (MTOCs), leukocytes mainly utilize centrosomes for sites of microtubule nucleation. Yet, MTOC localization as well as microtubule organization and dynamics are highly plastic in leukocytes thus allowing the cells to adapt to different environmental constraints. Here we summarize our current knowledge on microtubule organization and dynamics during immune processes and how these microtubule arrays affect immune cell effector functions. We particularly highlight emerging concepts of microtubule involvement during maintenance of cell shape and physical coherence.
Language	English
Publishing date	2021-02-09
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2021.635511
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Article ; Online: Correlation Between Early Trends of a Prognostic Biomarker and Overall Survival in Non-Small-Cell Lung Cancer Clinical Trials.

Loureiro, Hugo / Kolben, Theresa M / Kiermaier, Astrid / Rüttinger, Dominik / Ahmidi, Narges / Becker, Tim / Bauer-Mehren, Anna

JCO clinical cancer informatics

2023 Volume 7, Page(s) e2300062

Abstract: Purpose: Overall survival (OS) is the primary end point in phase III oncology trials. Given low success rates, surrogate end points, such as progression-free survival or objective response rate, are used in early go/no-go decision making. Here, we ... ...

Abstract	Purpose: Overall survival (OS) is the primary end point in phase III oncology trials. Given low success rates, surrogate end points, such as progression-free survival or objective response rate, are used in early go/no-go decision making. Here, we investigate whether early trends of OS prognostic biomarkers, such as the ROPRO and DeepROPRO, can also be used for this purpose. Methods: Using real-world data, we emulated a series of 12 advanced non-small-cell lung cancer (aNSCLC) clinical trials, originally conducted by six different sponsors and evaluated four different mechanisms, in a total of 19,920 individuals. We evaluated early trends (until 6 months) of the OS biomarker alongside early OS within the joint model (JM) framework. Study-level estimates of early OS and ROPRO trends were correlated against the actual final OS hazard ratios (HRs). Results: We observed a strong correlation between the JM estimates and final OS HR at 3 months (adjusted Conclusion: We describe a pipeline to predict trial OS HRs using emulated aNSCLC studies and their early OS and OS biomarker trends. The method has the potential to accelerate and improve decision making in drug development.
MeSH term(s)	Humans ; Carcinoma, Non-Small-Cell Lung/therapy ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Prognosis ; Lung Neoplasms/therapy ; Lung Neoplasms/drug therapy ; Disease-Free Survival ; Biomarkers
Chemical Substances	Biomarkers
Language	English
Publishing date	2023-11-03
Publishing country	United States
Document type	Journal Article
ISSN	2473-4276
ISSN (online)	2473-4276
DOI	10.1200/CCI.23.00062
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Article ; Online: Fetal liver macrophages contribute to the hematopoietic stem cell niche by controlling granulopoiesis.

Kayvanjoo, Amir Hossein / Splichalova, Iva / Bejarano, David Alejandro / Huang, Hao / Mauel, Katharina / Makdissi, Nikola / Heider, David / Tew, Hui Ming / Balzer, Nora Reka / Greto, Eric / Osei-Sarpong, Collins / Baßler, Kevin / Schultze, Joachim L / Uderhardt, Stefan / Kiermaier, Eva / Beyer, Marc / Schlitzer, Andreas / Mass, Elvira

eLife

2024 Volume 13

Abstract: During embryogenesis, the fetal liver becomes the main hematopoietic organ, where stem and progenitor cells as well as immature and mature immune cells form an intricate cellular network. Hematopoietic stem cells (HSCs) reside in a specialized niche, ... ...

Abstract	During embryogenesis, the fetal liver becomes the main hematopoietic organ, where stem and progenitor cells as well as immature and mature immune cells form an intricate cellular network. Hematopoietic stem cells (HSCs) reside in a specialized niche, which is essential for their proliferation and differentiation. However, the cellular and molecular determinants contributing to this fetal HSC niche remain largely unknown. Macrophages are the first differentiated hematopoietic cells found in the developing liver, where they are important for fetal erythropoiesis by promoting erythrocyte maturation and phagocytosing expelled nuclei. Yet, whether macrophages play a role in fetal hematopoiesis beyond serving as a niche for maturing erythroblasts remains elusive. Here, we investigate the heterogeneity of macrophage populations in the murine fetal liver to define their specific roles during hematopoiesis. Using a single-cell omics approach combined with spatial proteomics and genetic fate-mapping models, we found that fetal liver macrophages cluster into distinct yolk sac-derived subpopulations and that long-term HSCs are interacting preferentially with one of the macrophage subpopulations. Fetal livers lacking macrophages show a delay in erythropoiesis and have an increased number of granulocytes, which can be attributed to transcriptional reprogramming and altered differentiation potential of long-term HSCs. Together, our data provide a detailed map of fetal liver macrophage subpopulations and implicate macrophages as part of the fetal HSC niche.
MeSH term(s)	Animals ; Mice ; Hematopoiesis/genetics ; Macrophages ; Hematopoietic Stem Cells ; Cell Differentiation ; Erythropoiesis ; Liver ; Stem Cell Niche/genetics
Language	English
Publishing date	2024-03-25
Publishing country	England
Document type	Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.86493
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Article ; Online: Die Bedeutung von Biobanken für die klinische Entwicklung.

Thomas, Marlene / Kiermaier, Astrid / Cannarile, Michael

Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz

2016 Volume 59, Issue 3, Page(s) 344–350

Abstract: Access to samples in biobanks and collection of samples for evaluation of biomarkers in clinical trials are an essential basis for the identification and development of biomarkers. From the perspective of a research-based pharmaceutical company ... ...

Title translation	The significance of biobanks for clinical development.
Abstract	Access to samples in biobanks and collection of samples for evaluation of biomarkers in clinical trials are an essential basis for the identification and development of biomarkers. From the perspective of a research-based pharmaceutical company identification of biomarkers and the accompanying diagnostics are an essential prerequisite for the further evolution of personalised healthcare-and the key to more effective and efficient healthcare. Research-based pharmaceutical companies can basically use four types of biobanks: biobanks of university hospitals, commercial providers, collaborative groups and company-owned biobanks. Areas of application, arising from the use of biobanks in the context of clinical development, are collection of prevalence data, evaluation of biomarker stability in different disease stages, technical validation of assays, an optimized course of clinical studies by focusing on defined, biomarker-stratified groups of patients and pharmacogenetic research. Challenges are, in particular, the availability of clinically annotated samples and tissue matching blood samples, in addition to sample quality, number and amount. An acceptable legal and regulatory framework, as well as the positive perception of biomarker data by politicians and the public, are important prerequisites for translational research for identification of biomarkers in clinical studies. Also, the early establishment of research alliances between academia and the pharmaceutical industry are required to transfer research results in new strategies for prevention, diagnosis and treatment of patients.
MeSH term(s)	Biological Specimen Banks/organization & administration ; Biomedical Research/organization & administration ; Drug Industry/organization & administration ; Germany ; Humans ; Interinstitutional Relations ; Internationality ; Models, Organizational ; Tissue and Organ Procurement/organization & administration ; Translational Medical Research/organization & administration
Language	German
Publishing date	2016-03
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1461973-8
ISSN	1437-1588 ; 1436-9990
ISSN (online)	1437-1588
ISSN	1436-9990
DOI	10.1007/s00103-015-2304-5
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Article ; Online: Pertuzumab, trastuzumab, and chemotherapy in HER2-positive gastric/gastroesophageal junction cancer: end-of-study analysis of the JACOB phase III randomized clinical trial.

Tabernero, Josep / Hoff, Paulo M / Shen, Lin / Ohtsu, Atsushi / Shah, Manish A / Siddiqui, Asna / Heeson, Sarah / Kiermaier, Astrid / Macharia, Harrison / Restuccia, Eleonora / Kang, Yoon-Koo

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association

2022 Volume 26, Issue 1, Page(s) 123–131

Abstract: Background: Dual-targeted anti-HER2 therapy significantly improves outcomes in HER2-positive breast cancer and could be beneficial in other HER2-positive cancers. JACOB's end-of study analyses aimed to evaluate the long-term efficacy and safety of ... ...

Abstract	Background: Dual-targeted anti-HER2 therapy significantly improves outcomes in HER2-positive breast cancer and could be beneficial in other HER2-positive cancers. JACOB's end-of study analyses aimed to evaluate the long-term efficacy and safety of pertuzumab plus trastuzumab and chemotherapy for previously untreated HER2-positive metastatic gastric or gastroesophageal junction cancer. Methods: Eligible patients were randomized 1:1 to pertuzumab/placebo plus trastuzumab and chemotherapy every 3 weeks. Primary endpoint: overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and safety. Results: The intention-to-treat population comprised 388 patients in the pertuzumab arm and 392 in the placebo arm. The safety population comprised 385 and 388 patients, respectively. Median follow-up was ≥ 44.4 months. Median OS was increased by 3.9 months (hazard ratio 0.85 [95% confidence intervals, 0.72-0.99]) and median PFS by 1.3 months (hazard ratio 0.73 [95% confidence intervals, 0.62-0.85]) in the pertuzumab vs. the placebo arm. ORR was numerically higher (57.0% vs. 48.6%) and median DoR 1.8 months longer with pertuzumab treatment. There was a trend for more favorable hazard ratios in certain subgroups related to HER2 amplification/overexpression. Safety was comparable between arms, except for serious and grade 3-5 adverse events, and any-grade diarrhea, which were more frequent with pertuzumab. Conclusions: JACOB did not meet its primary endpoint. Nonetheless, the study continues to demonstrate some, albeit limited, evidence of treatment activity and an acceptable safety profile for pertuzumab plus trastuzumab and chemotherapy in previously untreated HER2-positive metastatic gastric or gastroesophageal junction cancer after long-term follow-up. Trial registration NCT01774786; https://clinicaltrials.gov/ct2/show/NCT01774786 .
MeSH term(s)	Humans ; Female ; Trastuzumab ; Receptor, ErbB-2 ; Stomach Neoplasms/pathology ; Biomarkers, Tumor ; Breast Neoplasms/pathology ; Esophageal Neoplasms/pathology ; Esophagogastric Junction/pathology ; Antineoplastic Combined Chemotherapy Protocols
Chemical Substances	Trastuzumab (P188ANX8CK) ; pertuzumab (K16AIQ8CTM) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Biomarkers, Tumor
Language	English
Publishing date	2022-09-06
Publishing country	Japan
Document type	Randomized Controlled Trial ; Clinical Trial, Phase III ; Journal Article ; Comment
ZDB-ID	1463526-4
ISSN	1436-3305 ; 1436-3291
ISSN (online)	1436-3305
ISSN	1436-3291
DOI	10.1007/s10120-022-01335-4
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Book ; Online: A subspace code of size $333$ in the setting of a binary $q$-analog of the Fano plane

Heinlein, Daniel / Kiermaier, Michael / Kurz, Sascha / Wassermann, Alfred

2017

Abstract: We show that there is a binary subspace code of constant dimension 3 in ambient dimension 7, having minimum distance 4 and cardinality 333, i.e., $333 \le A_2(7,4;3)$, which improves the previous best known lower bound of 329. Moreover, if a code with ... ...

Abstract	We show that there is a binary subspace code of constant dimension 3 in ambient dimension 7, having minimum distance 4 and cardinality 333, i.e., $333 \le A_2(7,4;3)$, which improves the previous best known lower bound of 329. Moreover, if a code with these parameters has at least 333 elements, its automorphism group is in one of $31$ conjugacy classes. This is achieved by a more general technique for an exhaustive search in a finite group that does not depend on the enumeration of all subgroups. Comment: 18 pages; typos corrected
Keywords	Mathematics - Combinatorics ; Computer Science - Information Theory ; 51E20 ; 05B07 ; 11T71 ; 94B25
Publishing date	2017-08-21
Publishing country	us
Document type	Book ; Online
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Article ; Online: Reply to a. Avan et Al.

Baselga, José / Clark, Emma / Kiermaier, Astrid / Swain, Sandra M

Journal of clinical oncology : official journal of the American Society of Clinical Oncology

2015 Volume 33, Issue 15, Page(s) 1712

MeSH term(s)	Antibodies, Monoclonal, Humanized/therapeutic use ; Antineoplastic Agents/therapeutic use ; Biomarkers, Tumor/analysis ; Breast Neoplasms/drug therapy ; Female ; Humans ; Receptor, ErbB-2/analysis
Chemical Substances	Antibodies, Monoclonal, Humanized ; Antineoplastic Agents ; Biomarkers, Tumor ; Receptor, ErbB-2 (EC 2.7.10.1)
Language	English
Publishing date	2015-04-13
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	604914-x
ISSN	1527-7755 ; 0732-183X
ISSN (online)	1527-7755
ISSN	0732-183X
DOI	10.1200/JCO.2015.60.8398
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Article ; Online: Multiple centrosomes enhance migration and immune cell effector functions of mature dendritic cells.

Weier, Ann-Kathrin / Homrich, Mirka / Ebbinghaus, Stephanie / Juda, Pavel / Miková, Eliška / Hauschild, Robert / Zhang, Lili / Quast, Thomas / Mass, Elvira / Schlitzer, Andreas / Kolanus, Waldemar / Burgdorf, Sven / Gruß, Oliver J / Hons, Miroslav / Wieser, Stefan / Kiermaier, Eva

The Journal of cell biology

2022 Volume 221, Issue 12

Abstract: Centrosomes play a crucial role during immune cell interactions and initiation of the immune response. In proliferating cells, centrosome numbers are tightly controlled and generally limited to one in G1 and two prior to mitosis. Defects in regulating ... ...

Abstract	Centrosomes play a crucial role during immune cell interactions and initiation of the immune response. In proliferating cells, centrosome numbers are tightly controlled and generally limited to one in G1 and two prior to mitosis. Defects in regulating centrosome numbers have been associated with cell transformation and tumorigenesis. Here, we report the emergence of extra centrosomes in leukocytes during immune activation. Upon antigen encounter, dendritic cells pass through incomplete mitosis and arrest in the subsequent G1 phase leading to tetraploid cells with accumulated centrosomes. In addition, cell stimulation increases expression of polo-like kinase 2, resulting in diploid cells with two centrosomes in G1-arrested cells. During cell migration, centrosomes tightly cluster and act as functional microtubule-organizing centers allowing for increased persistent locomotion along gradients of chemotactic cues. Moreover, dendritic cells with extra centrosomes display enhanced secretion of inflammatory cytokines and optimized T cell responses. Together, these results demonstrate a previously unappreciated role of extra centrosomes for regular cell and tissue homeostasis.
MeSH term(s)	Cell Cycle Checkpoints ; Cell Movement ; Centrosome/metabolism ; Chemotaxis ; Cytokines/metabolism ; Dendritic Cells/metabolism ; Humans ; Microtubule-Organizing Center ; Mitosis ; Protein Serine-Threonine Kinases/metabolism ; T-Lymphocytes/metabolism
Chemical Substances	Cytokines ; PLK2 protein, human (EC 2.7.11.-) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2022-10-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.202107134
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Article ; Online: Creld2 function during unfolded protein response is essential for liver metabolism homeostasis.

Kern, Paul / Balzer, Nora R / Blank, Nelli / Cygon, Cornelia / Wunderling, Klaus / Bender, Franziska / Frolov, Alex / Sowa, Jan-Peter / Bonaguro, Lorenzo / Ulas, Thomas / Homrich, Mirka / Kiermaier, Eva / Thiele, Christoph / Schultze, Joachim L / Canbay, Ali / Bauer, Reinhard / Mass, Elvira

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2021 Volume 35, Issue 10, Page(s) e21939

Abstract: The unfolded protein response (UPR) is associated with hepatic metabolic function, yet it is not well understood how endoplasmic reticulum (ER) disturbance might influence metabolic homeostasis. Here, we describe the physiological function of Cysteine- ... ...

Abstract	The unfolded protein response (UPR) is associated with hepatic metabolic function, yet it is not well understood how endoplasmic reticulum (ER) disturbance might influence metabolic homeostasis. Here, we describe the physiological function of Cysteine-rich with EGF-like domains 2 (Creld2), previously characterized as a downstream target of the ER-stress signal transducer Atf6. To this end, we generated Creld2-deficient mice and induced UPR by injection of tunicamycin. Creld2 augments protein folding and creates an interlink between the UPR axes through its interaction with proteins involved in the cellular stress response. Thereby, Creld2 promotes tolerance to ER stress and recovery from acute stress. Creld2-deficiency leads to a dysregulated UPR and causes the development of hepatic steatosis during ER stress conditions. Moreover, Creld2-dependent enhancement of the UPR assists in the regulation of energy expenditure. Furthermore, we observed a sex dimorphism in human and mouse livers with only male patients showing an accumulation of CRELD2 protein during the progression from non-alcoholic fatty liver disease to non-alcoholic steatohepatitis and only male Creld2-deficient mice developing hepatic steatosis upon aging. These results reveal a Creld2 function at the intersection between UPR and metabolic homeostasis and suggest a mechanism in which chronic ER stress underlies fatty liver disease in males.
MeSH term(s)	Aging ; Animals ; Cell Adhesion Molecules/metabolism ; Disease Progression ; Endoplasmic Reticulum Stress ; Extracellular Matrix Proteins/metabolism ; Fatty Liver ; Homeostasis ; Humans ; Liver/metabolism ; Male ; Mice ; Non-alcoholic Fatty Liver Disease ; Unfolded Protein Response
Chemical Substances	CRELD2 protein, human ; CRELD2 protein, mouse ; Cell Adhesion Molecules ; Extracellular Matrix Proteins
Language	English
Publishing date	2021-10-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.202002713RR
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Article ; Online: Microtubules control cellular shape and coherence in amoeboid migrating cells.

Kopf, Aglaja / Renkawitz, Jörg / Hauschild, Robert / Girkontaite, Irute / Tedford, Kerry / Merrin, Jack / Thorn-Seshold, Oliver / Trauner, Dirk / Häcker, Hans / Fischer, Klaus-Dieter / Kiermaier, Eva / Sixt, Michael

The Journal of cell biology

2020 Volume 219, Issue 6

Abstract: Cells navigating through complex tissues face a fundamental challenge: while multiple protrusions explore different paths, the cell needs to avoid entanglement. How a cell surveys and then corrects its own shape is poorly understood. Here, we demonstrate ...

Abstract	Cells navigating through complex tissues face a fundamental challenge: while multiple protrusions explore different paths, the cell needs to avoid entanglement. How a cell surveys and then corrects its own shape is poorly understood. Here, we demonstrate that spatially distinct microtubule dynamics regulate amoeboid cell migration by locally promoting the retraction of protrusions. In migrating dendritic cells, local microtubule depolymerization within protrusions remote from the microtubule organizing center triggers actomyosin contractility controlled by RhoA and its exchange factor Lfc. Depletion of Lfc leads to aberrant myosin localization, thereby causing two effects that rate-limit locomotion: (1) impaired cell edge coordination during path finding and (2) defective adhesion resolution. Compromised shape control is particularly hindering in geometrically complex microenvironments, where it leads to entanglement and ultimately fragmentation of the cell body. We thus demonstrate that microtubules can act as a proprioceptive device: they sense cell shape and control actomyosin retraction to sustain cellular coherence.
MeSH term(s)	Actomyosin/metabolism ; Animals ; Cell Adhesion/physiology ; Cell Movement/physiology ; Cell Shape/physiology ; Cells, Cultured ; Dendritic Cells/cytology ; Dendritic Cells/drug effects ; Dendritic Cells/metabolism ; Female ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microtubule-Organizing Center/drug effects ; Microtubule-Organizing Center/metabolism ; Microtubules/drug effects ; Microtubules/metabolism ; Nocodazole/pharmacology ; Protein Binding ; Rho Guanine Nucleotide Exchange Factors/deficiency ; Rho Guanine Nucleotide Exchange Factors/genetics ; Rho Guanine Nucleotide Exchange Factors/metabolism ; rhoA GTP-Binding Protein/metabolism
Chemical Substances	Arhgef2 protein, mouse ; Rho Guanine Nucleotide Exchange Factors ; Actomyosin (9013-26-7) ; RhoA protein, mouse (EC 3.6.5.2) ; rhoA GTP-Binding Protein (EC 3.6.5.2) ; Nocodazole (SH1WY3R615)
Language	English
Publishing date	2020-04-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.201907154
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