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Research Articles

Timed Ang2-Targeted Therapy Identifies the Angiopoietin–Tie Pathway as Key Regulator of Fatal Lymphogenous Metastasis

Nicolas Gengenbacher, Mahak Singhal, Carolin Mogler, Ling Hai, Laura Milde, Ashik Ahmed Abdul Pari, Eva Besemfelder, Claudine Fricke, Daniel Baumann, Stephanie Gehrs, Jochen Utikal, Moritz Felcht, Junhao Hu, Matthias Schlesner, Rienk Offringa, Sudhakar R. Chintharlapalli and Hellmut G. Augustin
Nicolas Gengenbacher
1Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.
2Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
3Faculty of Biosciences, Heidelberg University, Mannheim, Germany.
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Mahak Singhal
1Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.
2Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
3Faculty of Biosciences, Heidelberg University, Mannheim, Germany.
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  • ORCID record for Mahak Singhal
Carolin Mogler
4Institute of Pathology, TUM School of Medicine, Munich, Germany.
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Ling Hai
5Junior Group Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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Laura Milde
1Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.
2Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
3Faculty of Biosciences, Heidelberg University, Mannheim, Germany.
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Ashik Ahmed Abdul Pari
1Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.
2Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
3Faculty of Biosciences, Heidelberg University, Mannheim, Germany.
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Eva Besemfelder
1Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.
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Claudine Fricke
1Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.
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Daniel Baumann
3Faculty of Biosciences, Heidelberg University, Mannheim, Germany.
6Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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Stephanie Gehrs
1Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.
2Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
3Faculty of Biosciences, Heidelberg University, Mannheim, Germany.
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Jochen Utikal
7Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
8Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
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Moritz Felcht
2Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
8Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
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Junhao Hu
9Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
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Matthias Schlesner
5Junior Group Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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Rienk Offringa
6Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
10Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany.
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Sudhakar R. Chintharlapalli
11Eli Lilly and Company, Indianapolis, Indiana.
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Hellmut G. Augustin
1Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.
2Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
12German Cancer Consortium, Heidelberg, Germany.
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  • For correspondence: augustin@angioscience.de
DOI: 10.1158/2159-8290.CD-20-0122 Published February 2021
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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

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Cancer Discov 2021;11:424–45

  • Received January 30, 2020.
  • Revision received August 13, 2020.
  • Accepted October 9, 2020.
  • Published first October 26, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Discovery: 11 (2)
February 2021
Volume 11, Issue 2
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Timed Ang2-Targeted Therapy Identifies the Angiopoietin–Tie Pathway as Key Regulator of Fatal Lymphogenous Metastasis
Nicolas Gengenbacher, Mahak Singhal, Carolin Mogler, Ling Hai, Laura Milde, Ashik Ahmed Abdul Pari, Eva Besemfelder, Claudine Fricke, Daniel Baumann, Stephanie Gehrs, Jochen Utikal, Moritz Felcht, Junhao Hu, Matthias Schlesner, Rienk Offringa, Sudhakar R. Chintharlapalli and Hellmut G. Augustin
Cancer Discov February 1 2021 (11) (2) 424-445; DOI: 10.1158/2159-8290.CD-20-0122

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Timed Ang2-Targeted Therapy Identifies the Angiopoietin–Tie Pathway as Key Regulator of Fatal Lymphogenous Metastasis
Nicolas Gengenbacher, Mahak Singhal, Carolin Mogler, Ling Hai, Laura Milde, Ashik Ahmed Abdul Pari, Eva Besemfelder, Claudine Fricke, Daniel Baumann, Stephanie Gehrs, Jochen Utikal, Moritz Felcht, Junhao Hu, Matthias Schlesner, Rienk Offringa, Sudhakar R. Chintharlapalli and Hellmut G. Augustin
Cancer Discov February 1 2021 (11) (2) 424-445; DOI: 10.1158/2159-8290.CD-20-0122
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