Anja Runge

Heidelberg University

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Hellmut G. Augustin

Heidelberg University

Carolin Mogler

Technical University of Munich

Matthias Wieland

Cornell University

Peter Schirmacher

Heidelberg University

Dorde Komljenovic

German Cancer Research Center

M. Celeste Simon

University of Pennsylvania

Sergij Goerdt

University Hospital Heidelberg

Bernd Arnold

German Cancer Research Center

Cyrill Géraud

University Medical Centre Mannheim

André Neumann

Center for NanoScience

Cooperative Institutions

Heidelberg University

University Hospital Heidelberg

German Cancer Research Center

University Medical Centre Mannheim

University of Pennsylvania

DKFZ-ZMBH Alliance

Max Planck Institute of Molecular Cell Biology and Genetics

Heidelberg University

Cancer Research Institute

Medizinische Fakultät Mannheim

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Data from An Inducible Hepatocellular Carcinoma Model for Preclinical Evaluation of Antiangiogenic Therapy in Adult Mice

Anja Runge Junhao Hu Matthias Wieland Jan-Philip Bergeest Carolin Mogler

<div>Abstract<p>The limited availability of experimental tumor models that faithfully mimic the progression of human tumors and their response to therapy remains a major bottleneck to the clinical translation and application of novel therapeutic principles. To address this challenge in hepatocellular carcinoma (HCC), one of the deadliest and most common cancers in the world, we developed and validated an inducible model of hepatocarcinogenesis in adult mice. Tumorigenesis was triggered by intravenous adenoviral delivery of Cre recombinase in transgenic mice expressing the hepatocyte-specific albumin promoter, a loxP-flanked stop cassette, and the SV40 large T-antigen (iAST). Cre recombinase–mediated excision of the stop cassette led to a transient viral hepatitis and resulted in multinodular tumorigenesis within 5 to 8 weeks. Tumor nodules with histologic characteristics of human HCC established a functional vasculature by cooption, remodeling, and angiogenic expansion of the preexisting sinusoidal liver vasculature with increasing signs of vascular immaturity during tumor progression. Treatment of mice with sorafenib rapidly resulted in the induction of vascular regression, inhibition of tumor growth, and enhanced overall survival. Vascular regression was characterized by loss of endothelial cells leaving behind avascular type IV collagen–positive empty sleeves with remaining pericytes. Sorafenib treatment led to transcriptional changes of <i>Igf1, Id1</i>, and <i>cMet</i> over time, which may reflect the emergence of potential escape mechanisms. Taken together, our results established the iAST model of inducible hepatocarcinogenesis as a robust and versatile preclinical model to study HCC progression and validate novel therapies. <i>Cancer Res; 74(15); 4157–69. ©2014 AACR</i>.</p></div>

Antiangiogenic therapy

10.1158/0008-5472.c.6505161

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Hepatic stellate cell‐expressed endosialin balances fibrogenesis and hepatocyte proliferation during liver damage

EMBO Molecular Medicine (2015)

Carolin Mogler Matthias Wieland Courtney König Junhao Hu Anja Runge

Abstract Liver fibrosis is a reversible wound‐healing response to injury reflecting the critical balance between liver repair and scar formation. Chronic damage leads to progressive substitution of liver parenchyma by scar tissue and ultimately results in liver cirrhosis. Stromal cells (hepatic stellate cells [ HSC ] and endothelial cells) have been proposed to control the balance between liver fibrosis and regeneration. Here, we show that endosialin, a C‐type lectin, expressed in the liver exclusively by HSC and portal fibroblasts, is upregulated in liver fibrosis in mouse and man. Chronic chemically induced liver damage resulted in reduced fibrosis and enhanced hepatocyte proliferation in endosialin‐deficient ( EN KO ) mice. Correspondingly, acute‐liver‐damage‐induced hepatocyte proliferation (partial hepatectomy) was increased in EN KO mice. A candidate‐based screen of known regulators of hepatocyte proliferation identified insulin‐like growth factor 2 ( IGF 2) as selectively endosialin‐dependent hepatocyte mitogen. Collectively, the study establishes a critical role of HSC in the reciprocal regulation of fibrogenesis vs. hepatocyte proliferation and identifies endosialin as a therapeutic target in non‐neoplastic settings.

Hepatic stellate cell

Liver cytology

10.15252/emmm.201404246

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Citations (63)

ARNT IS IMPORTANT FOR HEMATOPOIETIC AND VASCULAR DEVELOPMENT

Cardiovascular Pathology (2004)

Diana L. Ramírez‐Bergeron Anja Runge M. Celeste Simon

10.1016/j.carpath.2004.03.200

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EPAS1 Is Required for Spermatogenesis in the Postnatal Mouse Testis1

Biology of Reproduction (2010)

Michaela Gruber Lijoy K. Mathew Anja Runge Joseph A. Garcia M. Celeste Simon

Spermatogenesis, a process involving the differentiation of spermatogonial stem cells into mature spermatozoa, takes place throughout masculine life. A complex system in the testis, including endocrine signaling, physical interactions between germ and somatic cells, spermatocyte meiosis, and timely release of spermatozoa, controls this cycle. We demonstrate herein that decreased O(2) levels and Epas1 activation are critical components of spermatogenesis. Postnatal Epas1 ablation leads to male infertility, with reduced testis size and weight. While immature spermatogonia and spermatocytes are present in Epas1(Delta/Delta) testes, spermatid and spermatozoan numbers are dramatically reduced. This is not due to germ cell-intrinsic defects. Rather, Epas(Delta/Delta) Sertoli cells exhibit decreased ability to form tight junctions, thereby disrupting the blood-testis barrier necessary for proper spermatogenesis. Reduced numbers of tight junction complexes are due to decreased expression of multiple genes encoding tight junction proteins, including TJP1 (ZO1), TJP2 (ZO2), and occludin. Furthermore, Epas1(Delta/Delta) testes exhibit disrupted basement membranes surrounding the seminiferous tubules, causing the premature release of incompletely differentiated germ cells. We conclude that low O(2) levels in the male gonad regulate germ cell homeostasis in this organ via EPAS1.

Spermatocyte

Spermatid

SOX9

10.1095/biolreprod.109.079202

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Citations (35)

Author Correction: Reconstitution of Rab- and SNARE-dependent membrane fusion by synthetic endosomes

Nature (2024)

Takeshi Ohya Marta Miączyńska Ünal Coskun Barbara Lommer Anja Runge

Rab

10.1038/s41586-024-07063-2

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Endothelial Cell-Derived Angiopoietin-2 Controls Liver Regeneration as a Spatiotemporal Rheostat

Science (2014)

Junhao Hu Kshitij Srivastava Matthias Wieland Anja Runge Carolin Mogler

Liver regeneration requires spatially and temporally precisely coordinated proliferation of the two major hepatic cell populations, hepatocytes and liver sinusoidal endothelial cells (LSECs), to reconstitute liver structure and function. The underlying mechanisms of this complex molecular cross-talk remain elusive. Here, we show that the expression of Angiopoietin-2 (Ang2) in LSECs is dynamically regulated after partial hepatectomy. During the early inductive phase of liver regeneration, Ang2 down-regulation leads to reduced LSEC transforming growth factor-β1 production, enabling hepatocyte proliferation by releasing an angiocrine proliferative brake. During the later angiogenic phase of liver regeneration, recovery of endothelial Ang2 expression enables regenerative angiogenesis by controlling LSEC vascular endothelial growth factor receptor 2 expression. The data establish LSECs as a dynamic rheostat of liver regeneration, spatiotemporally orchestrating hepatocyte and LSEC proliferation through angiocrine- and autocrine-acting Ang2, respectively.

Liver Regeneration

Angiopoietin receptor

Angiopoietin

Kupffer cell

10.1126/science.1244880

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Citations (279)

An Inducible Hepatocellular Carcinoma Model for Preclinical Evaluation of Antiangiogenic Therapy in Adult Mice

Cancer Research (2014)

Anja Runge Junhao Hu Matthias Wieland Jan-Philip Bergeest Carolin Mogler

The limited availability of experimental tumor models that faithfully mimic the progression of human tumors and their response to therapy remains a major bottleneck to the clinical translation and application of novel therapeutic principles. To address this challenge in hepatocellular carcinoma (HCC), one of the deadliest and most common cancers in the world, we developed and validated an inducible model of hepatocarcinogenesis in adult mice. Tumorigenesis was triggered by intravenous adenoviral delivery of Cre recombinase in transgenic mice expressing the hepatocyte-specific albumin promoter, a loxP-flanked stop cassette, and the SV40 large T-antigen (iAST). Cre recombinase-mediated excision of the stop cassette led to a transient viral hepatitis and resulted in multinodular tumorigenesis within 5 to 8 weeks. Tumor nodules with histologic characteristics of human HCC established a functional vasculature by cooption, remodeling, and angiogenic expansion of the preexisting sinusoidal liver vasculature with increasing signs of vascular immaturity during tumor progression. Treatment of mice with sorafenib rapidly resulted in the induction of vascular regression, inhibition of tumor growth, and enhanced overall survival. Vascular regression was characterized by loss of endothelial cells leaving behind avascular type IV collagen-positive empty sleeves with remaining pericytes. Sorafenib treatment led to transcriptional changes of Igf1, Id1, and cMet over time, which may reflect the emergence of potential escape mechanisms. Taken together, our results established the iAST model of inducible hepatocarcinogenesis as a robust and versatile preclinical model to study HCC progression and validate novel therapies.

Cre recombinase

Tumor progression

Liver Cancer

Liver tumor

10.1158/0008-5472.can-13-2311

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Citations (27)

Endothelial deletion of hypoxia-inducible factor–2α (HIF-2α) alters vascular function and tumor angiogenesis

Blood (2009)

Nicolas Skuli Liping Liu Anja Runge Tao Wang Lijun Yuan

Vascular permeability

Angiopoietin