15 results on '"Nicolas Gengenbacher"'
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2. Supplementary Figures from Timed Ang2-Targeted Therapy Identifies the Angiopoietin–Tie Pathway as Key Regulator of Fatal Lymphogenous Metastasis
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Hellmut G. Augustin, Sudhakar R. Chintharlapalli, Rienk Offringa, Matthias Schlesner, Junhao Hu, Moritz Felcht, Jochen Utikal, Stephanie Gehrs, Daniel Baumann, Claudine Fricke, Eva Besemfelder, Ashik Ahmed Abdul Pari, Laura Milde, Ling Hai, Carolin Mogler, Mahak Singhal, and Nicolas Gengenbacher
- Abstract
Supplementary Figures S1 - S28
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- 2023
- Full Text
- View/download PDF
3. Data from Timed Ang2-Targeted Therapy Identifies the Angiopoietin–Tie Pathway as Key Regulator of Fatal Lymphogenous Metastasis
- Author
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Hellmut G. Augustin, Sudhakar R. Chintharlapalli, Rienk Offringa, Matthias Schlesner, Junhao Hu, Moritz Felcht, Jochen Utikal, Stephanie Gehrs, Daniel Baumann, Claudine Fricke, Eva Besemfelder, Ashik Ahmed Abdul Pari, Laura Milde, Ling Hai, Carolin Mogler, Mahak Singhal, and Nicolas Gengenbacher
- Abstract
Recent clinical and preclinical advances have highlighted the existence of a previously hypothesized lymphogenous route of metastasis. However, due to a lack of suitable preclinical modeling tools, its contribution to long-term disease outcome and relevance for therapy remain controversial. Here, we established a genetically engineered mouse model (GEMM) fragment–based tumor model uniquely sustaining a functional network of intratumoral lymphatics that facilitates seeding of fatal peripheral metastases. Multiregimen survival studies and correlative patient data identified primary tumor–derived Angiopoietin-2 (Ang2) as a potent therapeutic target to restrict lymphogenous tumor cell dissemination. Mechanistically, tumor-associated lymphatic endothelial cells (EC), in contrast to blood vascular EC, were found to be critically addicted to the Angiopoietin–Tie pathway. Genetic manipulation experiments in combination with single-cell mapping revealed agonistically acting Ang2–Tie2 signaling as key regulator of lymphatic maintenance. Correspondingly, acute presurgical Ang2 neutralization was sufficient to prolong survival by regressing established intratumoral lymphatics, hence identifying a therapeutic regimen that warrants further clinical evaluation.Significance:Exploiting multiple mouse tumor models including a unique GEMM-derived allograft system in combination with preclinical therapy designs closely matching the human situation, this study provides fundamental insight into the biology of tumor-associated lymphatic EC and defines an innovative presurgical therapeutic window of migrastatic Ang2 neutralization to restrict lymphogenous metastasis.This article is highlighted in the In This Issue feature, p. 211
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- 2023
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4. Data from Tumor Cell–Derived Angiopoietin-2 Promotes Metastasis in Melanoma
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Moritz Felcht, Hellmut G. Augustin, Kairbaan M. Hodivala-Dilke, Sergij Goerdt, Markus Thomas, Jochen Utikal, Cyrill Géraud, Dorothee Terhardt, Louise E. Reynolds, Nicolas Gengenbacher, Anja Gampp, Benjamin Schieb, Carolin Mogler, Corinne Hübers, Mahak Singhal, and Ashik Ahmed Abdul Pari
- Abstract
The angiopoietin (Angpt)–TIE signaling pathway controls vascular maturation and maintains the quiescent phenotype of resting vasculature. The contextual agonistic and antagonistic Tie2 ligand ANGPT2 is believed to be exclusively produced by endothelial cells, disrupting constitutive ANGPT1–TIE2 signaling to destabilize the microvasculature during pathologic disorders like inflammation and cancer. However, scattered reports have also portrayed tumor cells as a source of ANGPT2. Employing ISH-based detection of ANGPT2, we found strong tumor cell expression of ANGPT2 in a subset of patients with melanoma. Comparative analysis of biopsies revealed a higher fraction of ANGPT2-expressing tumor cells in metastatic versus primary sites. Tumor cell–expressed Angpt2 was dispensable for primary tumor growth, yet in-depth analysis of primary tumors revealed enhanced intratumoral necrosis upon silencing of tumor cell Angpt2 expression in the absence of significant immune and vascular alterations. Global transcriptional profiling of Angpt2-deficient tumor cells identified perturbations in redox homeostasis and an increased response to cellular oxidative stress. Ultrastructural analyses illustrated a significant increase of dysfunctional mitochondria in Angpt2-silenced tumor cells, thereby resulting in enhanced reactive oxygen species (ROS) production and downstream MAPK stress signaling. Functionally, enhanced ROS in Angpt2-silenced tumor cells reduced colonization potential in vitro and in vivo. Taken together, these findings uncover the hitherto unappreciated role of tumor cell–expressed ANGPT2 as an autocrine-positive regulator of metastatic colonization and validate ANGPT2 as a therapeutic target for a well-defined subset of patients with melanoma.Significance:This study reveals that tumor cells can be a source of ANGPT2 in the tumor microenvironment and that tumor cell-derived ANGPT2 augments metastatic colonization by protecting tumor cells from oxidative stress.
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- 2023
- Full Text
- View/download PDF
5. Supplementary Data from Tumor Cell–Derived Angiopoietin-2 Promotes Metastasis in Melanoma
- Author
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Moritz Felcht, Hellmut G. Augustin, Kairbaan M. Hodivala-Dilke, Sergij Goerdt, Markus Thomas, Jochen Utikal, Cyrill Géraud, Dorothee Terhardt, Louise E. Reynolds, Nicolas Gengenbacher, Anja Gampp, Benjamin Schieb, Carolin Mogler, Corinne Hübers, Mahak Singhal, and Ashik Ahmed Abdul Pari
- Abstract
This file consists of supplementary figures (SF) 1-11 consisting of: SF1: Melanoma cells express ANGPT2 (A-F). SF2: Melanoma cell-expressed Angpt2 does not modulate tumor cell proliferation (A-B). SF3: Tumor cell knockdown of Angpt2 does not impact growth of primary tumors (A-J). SF4: Angpt2-depletion in melanoma cells does not affect primary tumor microenvironment (A-F). SF5: Angpt2-depletion alters pathways governing metastasis and oxidative stress (A-B). SF6: Angpt2 knockdown in tumor cells affects the cellular redox balance (A-G). SF7: Tumor cell-expressed Angpt2 alters mitochondrial dynamics (A-E). SF8: Tumor cell-expressed Angpt2 promotes metastasis (A-G). SF9: Tumor cell-expressed Angpt2 does not affect early stages of metastasis in vitro (A-H). SF10: Silencing of Angpt2 impairs invasion through the basement membrane and transmigration across the endothelial barrier (A-H). SF11: Silencing of Angpt2 reduces in vitro colony formation (A-F).
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- 2023
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6. Primary tumor-derived systemic nANGPTL4 inhibits metastasis
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Corinne Hübers, Ashik Ahmed Abdul Pari, Denise Grieshober, Martin Petkov, Alexander Schmidt, Tatjana Messmer, Christian Moritz Heyer, Sebastian Schölch, Stephanie S. Kapel, Nicolas Gengenbacher, Mahak Singhal, Benjamin Schieb, Claudine Fricke, Rainer Will, Kim Remans, Jochen Sven Utikal, Christoph Reissfelder, Matthias Schlesner, Kairbaan M. Hodivala-Dilke, Sander Kersten, Sergij Goerdt, Hellmut G. Augustin, and Moritz Felcht
- Subjects
Immunology ,Metabolism and Genomics ,Peptide Fragments ,Voeding, Metabolisme en Genomica ,Voeding ,Metabolisme en Genomica ,Neoplasms ,Biomarkers, Tumor ,Immunology and Allergy ,Humans ,Angiopoietin-Like Protein 4 ,Life Science ,Nutrition, Metabolism and Genomics ,ddc:004 ,Angiopoietins ,VLAG ,Nutrition - Abstract
Primary tumors and distant site metastases form a bidirectionally communicating system. Yet, the molecular mechanisms of this crosstalk are poorly understood. Here, we identified the proteolytically cleaved fragments of angiopoietin-like 4 (ANGPTL4) as contextually active protumorigenic and antitumorigenic contributors in this communication ecosystem. Preclinical studies in multiple tumor models revealed that the C-terminal fragment (cANGPTL4) promoted tumor growth and metastasis. In contrast, the N-terminal fragment of ANGPTL4 (nANGPTL4) inhibited metastasis and enhanced overall survival in a postsurgical metastasis model by inhibiting WNT signaling and reducing vascularity at the metastatic site. Tracing ANGPTL4 and its fragments in tumor patients detected full-length ANGPTL4 primarily in tumor tissues, whereas nANGPTL4 predominated in systemic circulation and correlated inversely with disease progression. The study highlights the spatial context of the proteolytic cleavage-dependent pro- and antitumorigenic functions of ANGPTL4 and identifies and validates nANGPTL4 as a novel biomarker of tumor progression and antimetastatic therapeutic agent.
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- 2023
7. Timed Ang2-Targeted Therapy Identifies the Angiopoietin–Tie Pathway as Key Regulator of Fatal Lymphogenous Metastasis
- Author
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Ling Hai, Matthias Schlesner, Stephanie Gehrs, Nicolas Gengenbacher, Daniel Baumann, Mahak Singhal, Rienk Offringa, Sudhakar Chintharlapalli, Hellmut G. Augustin, Junhao Hu, Claudine Fricke, Ashik Ahmed Abdul Pari, Jochen Utikal, Laura Milde, Moritz Felcht, Eva Besemfelder, and Carolin Mogler
- Subjects
0301 basic medicine ,Lung Neoplasms ,medicine.medical_treatment ,government.form_of_government ,Regulator ,Mice, Transgenic ,Mice, SCID ,Metastasis ,Targeted therapy ,Angiopoietin-2 ,Functional networks ,Angiopoietin ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,ddc:610 ,business.industry ,Endothelial Cells ,medicine.disease ,Receptor, TIE-2 ,Mice, Inbred C57BL ,Disease Models, Animal ,Lymphatic Endothelium ,030104 developmental biology ,Lymphatic system ,Oncology ,Lymphatic Metastasis ,030220 oncology & carcinogenesis ,Genetically Engineered Mouse ,Cancer research ,government ,Female ,business ,Signal Transduction - Abstract
Recent clinical and preclinical advances have highlighted the existence of a previously hypothesized lymphogenous route of metastasis. However, due to a lack of suitable preclinical modeling tools, its contribution to long-term disease outcome and relevance for therapy remain controversial. Here, we established a genetically engineered mouse model (GEMM) fragment–based tumor model uniquely sustaining a functional network of intratumoral lymphatics that facilitates seeding of fatal peripheral metastases. Multiregimen survival studies and correlative patient data identified primary tumor–derived Angiopoietin-2 (Ang2) as a potent therapeutic target to restrict lymphogenous tumor cell dissemination. Mechanistically, tumor-associated lymphatic endothelial cells (EC), in contrast to blood vascular EC, were found to be critically addicted to the Angiopoietin–Tie pathway. Genetic manipulation experiments in combination with single-cell mapping revealed agonistically acting Ang2–Tie2 signaling as key regulator of lymphatic maintenance. Correspondingly, acute presurgical Ang2 neutralization was sufficient to prolong survival by regressing established intratumoral lymphatics, hence identifying a therapeutic regimen that warrants further clinical evaluation. Significance: Exploiting multiple mouse tumor models including a unique GEMM-derived allograft system in combination with preclinical therapy designs closely matching the human situation, this study provides fundamental insight into the biology of tumor-associated lymphatic EC and defines an innovative presurgical therapeutic window of migrastatic Ang2 neutralization to restrict lymphogenous metastasis. This article is highlighted in the In This Issue feature, p. 211
- Published
- 2021
- Full Text
- View/download PDF
8. Tumor Cell–Derived Angiopoietin-2 Promotes Metastasis in Melanoma
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Anja Gampp, Moritz Felcht, Louise E. Reynolds, Jochen Utikal, Carolin Mogler, Hellmut G. Augustin, Dorothee Terhardt, Benjamin Schieb, Mahak Singhal, Corinne Hübers, Cyrill Géraud, Kairbaan Hodivala-Dilke, Markus Thomas, Sergij Goerdt, Nicolas Gengenbacher, and Ashik Ahmed Abdul Pari
- Subjects
0301 basic medicine ,Cancer Research ,Skin Neoplasms ,MAP Kinase Signaling System ,Biopsy ,Inflammation ,Kaplan-Meier Estimate ,Biology ,Article ,Metastasis ,Angiopoietin-2 ,Angiopoietin ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Cell Line, Tumor ,Human Umbilical Vein Endothelial Cells ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Gene silencing ,Melanoma ,Nevus ,Skin ,Tumor microenvironment ,Gene Expression Profiling ,medicine.disease ,Primary tumor ,3. Good health ,Autocrine Communication ,Disease Models, Animal ,030104 developmental biology ,Oncology ,Tissue Array Analysis ,Gene Knockdown Techniques ,030220 oncology & carcinogenesis ,Disease Progression ,Cancer research ,Female ,medicine.symptom ,Reactive Oxygen Species - Abstract
The angiopoietin (Angpt)–TIE signaling pathway controls vascular maturation and maintains the quiescent phenotype of resting vasculature. The contextual agonistic and antagonistic Tie2 ligand ANGPT2 is believed to be exclusively produced by endothelial cells, disrupting constitutive ANGPT1–TIE2 signaling to destabilize the microvasculature during pathologic disorders like inflammation and cancer. However, scattered reports have also portrayed tumor cells as a source of ANGPT2. Employing ISH-based detection of ANGPT2, we found strong tumor cell expression of ANGPT2 in a subset of patients with melanoma. Comparative analysis of biopsies revealed a higher fraction of ANGPT2-expressing tumor cells in metastatic versus primary sites. Tumor cell–expressed Angpt2 was dispensable for primary tumor growth, yet in-depth analysis of primary tumors revealed enhanced intratumoral necrosis upon silencing of tumor cell Angpt2 expression in the absence of significant immune and vascular alterations. Global transcriptional profiling of Angpt2-deficient tumor cells identified perturbations in redox homeostasis and an increased response to cellular oxidative stress. Ultrastructural analyses illustrated a significant increase of dysfunctional mitochondria in Angpt2-silenced tumor cells, thereby resulting in enhanced reactive oxygen species (ROS) production and downstream MAPK stress signaling. Functionally, enhanced ROS in Angpt2-silenced tumor cells reduced colonization potential in vitro and in vivo. Taken together, these findings uncover the hitherto unappreciated role of tumor cell–expressed ANGPT2 as an autocrine-positive regulator of metastatic colonization and validate ANGPT2 as a therapeutic target for a well-defined subset of patients with melanoma. Significance: This study reveals that tumor cells can be a source of ANGPT2 in the tumor microenvironment and that tumor cell-derived ANGPT2 augments metastatic colonization by protecting tumor cells from oxidative stress.
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- 2020
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9. Temporal multi-omics identifies LRG1 as a vascular niche instructor of metastasis
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Martin R. Sprick, Carolin Mogler, Mathias Heikenwalder, Stephen E. Moss, Jeroen Krijgsveld, Matthias Schlesner, David Kallenberg, Mahak Singhal, Hellmut G. Augustin, Barbara Leuchs, Ling Hai, Shubhada Rajabhau Kulkarni, Junhao Hu, Danijela Heide, Bianca J. Kuhn, Stephanie F. Preuß, John A. Greenwood, Nicolas Gengenbacher, Eva Besemfelder, Andreas Trumpp, Ashik Ahmed Abdul Pari, Elisa Espinet, Miki Kamiyama, and Carlotta Camilli
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Tumor cells ,General Medicine ,Biology ,medicine.disease ,Metastasis ,LRG1 ,Neoplasms ,Cancer research ,medicine ,Humans ,Multi omics ,Vascular niche ,ddc:610 ,Glycoproteins - Abstract
Metastasis is the primary cause of cancer-related mortality. Tumor cell interactions with cells of the vessel wall are decisive and potentially rate-limiting for metastasis. The molecular nature of this cross-talk is, beyond candidate gene approaches, hitherto poorly understood. Using endothelial cell (EC) bulk and single-cell transcriptomics in combination with serum proteomics, we traced the evolution of the metastatic vascular niche in surgical models of lung metastasis. Temporal multiomics revealed that primary tumors systemically reprogram the body’s vascular endothelium to perturb homeostasis and to precondition the vascular niche for metastatic growth. The vasculature with its enormous surface thereby serves as amplifier of tumor-induced instructive signals. Comparative analysis of lung EC gene expression and secretome identified the transforming growth factor–β (TGFβ) pathway specifier LRG1, leucine-rich alpha-2-glycoprotein 1, as an early instructor of metastasis. In the presence of a primary tumor, ECs systemically up-regulated LRG1 in a signal transducer and activator of transcription 3 (STAT3)–dependent manner. A meta-analysis of retrospective clinical studies revealed a corresponding up-regulation of LRG1 concentrations in the serum of patients with cancer. Functionally, systemic up-regulation of LRG1 promoted metastasis in mice by increasing the number of prometastatic neural/glial antigen 2 (NG2)
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- 2021
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10. Pericyte-expressed Tie2 controls angiogenesis and vessel maturation
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Kshitij Srivastava, Annegret Holm, Nicolas Gengenbacher, Stella Hertel, Junhao Hu, Tina Ruckdeschel, Martin Teichert, Soniya Savant, Zulfiyya Hasanov, Katharina Schlereth, Laura Milde, Arne Bartol, Hellmut G. Augustin, and Laura Stanicek
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0301 basic medicine ,Male ,Angiogenesis ,Science ,General Physics and Astronomy ,Neovascularization, Physiologic ,Mice, SCID ,General Biochemistry, Genetics and Molecular Biology ,Article ,Angiopoietin ,03 medical and health sciences ,medicine ,Human Umbilical Vein Endothelial Cells ,Gene silencing ,Animals ,Humans ,Protein kinase B ,Cells, Cultured ,Sprouting angiogenesis ,Multidisciplinary ,biology ,Neovascularization, Pathologic ,integumentary system ,Calpain ,General Chemistry ,Ribonuclease, Pancreatic ,Angiopoietin receptor ,Receptor, TIE-2 ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,surgical procedures, operative ,embryonic structures ,biology.protein ,cardiovascular system ,Female ,Pericyte ,sense organs ,Pericytes ,tissues - Abstract
The Tie receptors with their Angiopoietin ligands act as regulators of angiogenesis and vessel maturation. Tie2 exerts its functions through its supposed endothelial-specific expression. Yet, Tie2 is also expressed at lower levels by pericytes and it has not been unravelled through which mechanisms pericyte Angiopoietin/Tie signalling affects angiogenesis. Here we show that human and murine pericytes express functional Tie2 receptor. Silencing of Tie2 in pericytes results in a pro-migratory phenotype. Pericyte Tie2 controls sprouting angiogenesis in in vitro sprouting and in vivo spheroid assays. Tie2 downstream signalling in pericytes involves Calpain, Akt and FOXO3A. Ng2-Cre-driven deletion of pericyte-expressed Tie2 in mice transiently delays postnatal retinal angiogenesis. Yet, Tie2 deletion in pericytes results in a pronounced pro-angiogenic effect leading to enhanced tumour growth. Together, the data expand and revise the current concepts on vascular Angiopoietin/Tie signalling and propose a bidirectional, reciprocal EC-pericyte model of Tie2 signalling., The angiopoietins regulate vascular maturation, angiogenesis and lymphangiogenesis via their Tie receptors that were long believed to be endothelium-specific. Here the authors show that angiopoietins activate and control pericyte function through pericyte-expressed Tie2 triggering of Calpain, Akt and FOXO3A signalling cascades.
- Published
- 2017
11. Blocking Migration of Polymorphonuclear Myeloid-Derived Suppressor Cells Inhibits Mouse Melanoma Progression
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Jochen Utikal, Vera Petrova, Ihor Arkhypov, Ludovica Arpinati, Viktor Umansky, Nina Winkler, Merav E. Shaul, Christopher Groth, Zvi G Fridlender, Klara Diester, Nicolas Gengenbacher, Peter Altevogt, Hellmut G. Augustin, Samantha Lasser, and Rebekka Weber
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0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,PMN-MDSC ,lcsh:RC254-282 ,Article ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,melanoma ,medicine ,metastasis ,CXC chemokine receptors ,Tumor microenvironment ,CXCR2 ,immunosuppression ,business.industry ,Melanoma ,Immunotherapy ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,CXCL1 ,genetically engineered mouse model ,030104 developmental biology ,Oncology ,Tumor progression ,030220 oncology & carcinogenesis ,Cancer research ,Myeloid-derived Suppressor Cell ,immunotherapy ,business - Abstract
Simple Summary Myeloid-derived suppressor cells (MDSC) represent a heterogeneous myeloid cell population that is expanded in tumor bearing hosts and substantially contributes to immunosuppression, representing thereby a valuable therapeutic target. Our study analyzes polymorphonuclear (PMN) and monocytic (M) MDSC subsets regarding their immunosuppressive capacity and recruitment mechanisms in murine melanoma. The immunosuppressive activity of both subsets was comparable. We identified the C-X-C Motif Chemokine Receptor (CXCR) 2/chemokine C-X-C motif ligand (CXCL) 1 axis as an important mediator of PMN-MDSC recruitment. Inhibition of CXCR2 resulted in a decreased infiltration of tumors with PMN-MDSC and increased survival of melanoma bearing mice. Furthermore, adjuvant treatment of mice with resected tumors reduced the infiltration of pre-metastatic sites with PMN-MDSC and the occurrence of distant metastasis. The decrease in PMN-MDSC infiltration was accompanied by an increase in natural killer (NK) cell frequency, suggesting an important role of PMN-MDSC in suppressing the NK cell-mediated anti-tumor response. Abstract Background: Despite recent improvement in the treatment of malignant melanoma by immune-checkpoint inhibitors, the disease can progress due to an immunosuppressive tumor microenvironment (TME) mainly represented by myeloid-derived suppressor cells (MDSC). However, the relative contribution of the polymorphonuclear (PMN) and monocytic (M) MDSC subsets to melanoma progression is not clear. Here, we compared both subsets regarding their immunosuppressive capacity and recruitment mechanisms. Furthermore, we inhibited PMN-MDSC migration in vivo to determine its effect on tumor progression. Methods: Using the RET transgenic melanoma mouse model, we investigated the immunosuppressive function of MDSC subsets and chemokine receptor expression on these cells. The effect of CXCR2 inhibition on PMN-MDSC migration and tumor progression was studied in RET transgenic mice and in C57BL/6 mice after surgical resection of primary melanomas. Results: Immunosuppressive capacity of intratumoral M- and PMN-MDSC was comparable in melanoma bearing mice. Anti-CXCR2 therapy prolonged survival of these mice and decreased the occurrence of distant metastasis. Furthermore, this therapy reduced the infiltration of melanoma lesions and pre-metastatic sites with PMN-MDSC that was associated with the accumulation of natural killer (NK) cells. Conclusions: We provide evidence for the tumor−promoting properties of PMN-MDSC as well as for the anti-tumor effects upon their targeting in melanoma bearing mice.
- Published
- 2021
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12. Endothelial cell fitness dictates the source of regenerating liver vasculature
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Jianing Dai, Xiaoting Liu, Nicolas Gengenbacher, Mahak Singhal, Kai Jiang, Weiping Li, Lijian Hui, Hellmut G. Augustin, Susanne Bartels, Eva Besemfelder, Ashik Ahmed Abdul Pari, Hao He, Junhao Hu, and Donato Inverso
- Subjects
0301 basic medicine ,Endothelium ,medicine.medical_treatment ,Immunology ,Recombinant Granulocyte Colony-Stimulating Factor ,Biology ,News ,Models, Biological ,Insights ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine ,Immunology and Allergy ,Animals ,Hepatectomy ,Progenitor cell ,Bone Marrow Transplantation ,Mice, Knockout ,Regeneration (biology) ,Endothelial Cells ,Stem-cell therapy ,Liver regeneration ,3. Good health ,Liver Regeneration ,Endothelial stem cell ,030104 developmental biology ,medicine.anatomical_structure ,Liver ,030220 oncology & carcinogenesis ,Cancer research ,Bone marrow - Abstract
In this issue of JEM, Singhal et al. explore the cellular mechanisms involved in endothelial cell regeneration in the liver. Using a combination of myeloablative and nonmyeloablative approaches, the authors found that repair of the endothelium is mediated by endothelial cells themselves, but when injured, endothelial cells enlist myeloid counterparts that aid in vascular repair., In this issue of JEM, Singhal et al. (https://doi.org/10.1084/jem.20180008) explore the cellular mechanisms involved in endothelial cell regeneration in the liver. Using a combination of myeloablative and nonmyeloablative approaches, the authors found that repair of the endothelium is mediated by endothelial cells themselves, but when injured, endothelial cells enlist myeloid counterparts that aid in vascular repair.
- Published
- 2018
13. The ZEB1/miR-200c feedback loop regulates invasion via actin interacting proteins MYLK and TKS5
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Julia Kleemann, Simone Brabletz, Nicolas Gengenbacher, Marc P. Stemmler, Thomas Brabletz, and Vignesh Sundararajan
- Subjects
Epithelial-Mesenchymal Transition ,Myosin light-chain kinase ,Breast Neoplasms ,Biology ,Metastasis ,Antigens, CD ,Cell Line, Tumor ,medicine ,Humans ,epithelial to mesenchymal transition (EMT) ,ZEB1 ,Neoplasm Invasiveness ,Epithelial–mesenchymal transition ,Myosin-Light-Chain Kinase ,Cytoskeleton ,invadopodia ,Homeodomain Proteins ,Calcium-Binding Proteins ,Zinc Finger E-box-Binding Homeobox 1 ,Cancer ,MYLK ,Cadherins ,miR-200 ,medicine.disease ,Actin cytoskeleton ,Actins ,Cell biology ,Gene Expression Regulation, Neoplastic ,Adaptor Proteins, Vesicular Transport ,MicroRNAs ,HEK293 Cells ,Microscopy, Fluorescence ,Oncology ,Cancer cell ,Invadopodia ,Cancer research ,Female ,MYLK (MLCK) ,Transcription Factors ,Research Paper - Abstract
Epithelial to mesenchymal transition (EMT) is a developmental process which is aberrantly activated during cancer invasion and metastasis. Elevated expression of EMT-inducers like ZEB1 enables tumor cells to detach from the primary tumor and invade into the surrounding tissue. The main antagonist of ZEB1 in controlling EMT is the microRNA-200 family that is reciprocally linked to ZEB1 in a double negative feedback loop. Here, we further elucidate how the ZEB1/miR-200 feedback loop controls invasion of tumor cells. The process of EMT is attended by major changes in the actin cytoskeleton. Via in silico screening of genes encoding for actin interacting proteins, we identified two novel targets of miR-200c - TKS5 and MYLK (MLCK). Co-expression of both genes with ZEB1 was observed in several cancer cell lines as well as in breast cancer patients and correlated with low miR-200c levels. Depletion of TKS5 or MYLK in breast cancer cells reduced their invasive potential and their ability to form invadopodia. Whereas TKS5 is known to be a major component, we could identify MYLK as a novel player in invadopodia formation. In summary, TKS5 and MYLK represent two mediators of invasive behavior of cancer cells that are regulated by the ZEB1/miR-200 feedback loop.
- Published
- 2015
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14. Preclinical mouse solid tumour models: status quo, challenges and perspectives
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Nicolas Gengenbacher, Mahak Singhal, and Hellmut G. Augustin
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Status quo ,Systematic survey ,General Mathematics ,media_common.quotation_subject ,Translational Research, Biomedical ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Neoplasms ,Medicine ,Animals ,Humans ,media_common ,Solid tumour ,Human studies ,business.industry ,Tumor biology ,Experimental model ,Applied Mathematics ,Clinical trial ,Disease Models, Animal ,030104 developmental biology ,030220 oncology & carcinogenesis ,Observational study ,business ,Neuroscience - Abstract
Oncology research in humans is limited to analytical and observational studies for obvious ethical reasons, with therapy-focused clinical trials being the one exception to this rule. Preclinical mouse tumour models therefore serve as an indispensable intermediate experimental model system bridging more reductionist in vitro research with human studies. Based on a systematic survey of preclinical mouse tumour studies published in eight scientific journals in 2016, this Analysis provides an overview of how contemporary preclinical mouse tumour biology research is pursued. It thereby identifies some of the most important challenges in this field and discusses potential ways in which preclinical mouse tumour models could be improved for better relevance, reproducibility and translatability.
- Published
- 2017
15. Preclinical validation of a novel metastasis‐inhibiting Tie1 function‐blocking antibody
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Silvia La Porta, Anthony S. Fischl, Sudhakar Chintharlapalli, Hellmut G. Augustin, Nicolas Gengenbacher, Jingjing Shi, Benjamin Schieb, Stephanie Gehrs, Diane M. Bodenmiller, Miki Kamiyama, Mahak Singhal, and Eva Besemfelder
- Subjects
0301 basic medicine ,Medicine (General) ,Vascular Biology & Angiogenesis ,Angiogenesis ,Immunology ,QH426-470 ,TIE1 ,Metastasis ,Angiopoietin ,Angiopoietin-2 ,03 medical and health sciences ,angiogenesis ,Mice ,0302 clinical medicine ,R5-920 ,Report ,Neoplasms ,Blocking antibody ,medicine ,Genetics ,Angiopoietin-1 ,cancer ,metastasis ,Animals ,Humans ,Orphan receptor ,Neovascularization, Pathologic ,business.industry ,angiopoietin–Tie signaling ,Receptor, TIE-1 ,medicine.disease ,Primary tumor ,Receptor, TIE-2 ,Extravasation ,endothelial cells ,3. Good health ,030104 developmental biology ,Cancer research ,Molecular Medicine ,business ,030217 neurology & neurosurgery ,Gene Deletion - Abstract
The angiopoietin (Ang)–Tie pathway has been intensely pursued as candidate second‐generation anti‐angiogenic target. While much of the translational work has focused on the ligand Ang2, the clinical efficacy of Ang2‐targeting drugs is limited and failed to improve patient survival. In turn, the orphan receptor Tie1 remains therapeutically unexplored, although its endothelial‐specific genetic deletion has previously been shown to result in a strong reduction in metastatic growth. Here, we report a novel Tie1 function‐blocking antibody (AB‐Tie1‐39), which suppressed postnatal retinal angiogenesis. During primary tumor growth, neoadjuvant administration of AB‐Tie1‐39 strongly impeded systemic metastasis. Furthermore, the administration of AB‐Tie1‐39 in a perioperative therapeutic window led to a significant survival advantage as compared to control‐IgG‐treated mice. Additional in vivo experimental metastasis and in vitro transmigration assays concurrently revealed that AB‐Tie1‐39 treatment suppressed tumor cell extravasation at secondary sites. Taken together, the data phenocopy previous genetic work in endothelial Tie1 KO mice and thereby validate AB‐Tie1‐39 as a Tie1 function‐blocking antibody. The study establishes Tie1 as a therapeutic target for metastasis in a perioperative or neoadjuvant setting., The Angiopoietin‐Tie signaling pathway maintains vascular quiescence and is often dysregulated during tumor progression. A novel Tie1 function‐blocking antibody (AB‐Tie1‐39) shows anti‐metastatic efficacy and prolonged survival of preclinical metastasis models.
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