Journal Article

DKFZ-2020-02307

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Timed Ang2-targeted therapy identifies the Angiopoietin-Tie pathway as key regulator of fatal lymphogenous metastasis.

Gengenbacher, N. (First author)DKFZ* ; Singhal, M.DKFZ* ; Mogler, C. ; Hai, L.DKFZ* ; Milde, L.DKFZ* ; Abdul Pari, A. A.DKFZ* ; Besemfelder, E.DKFZ* ; Fricke, C.DKFZ* ; Baumann, D.DKFZ* ; Gehrs, S.DKFZ* ; Utikal, J.DKFZ* ; Felcht, M. ; Hu, J. ; Schlesner, M.DKFZ* ; Offringa, R.DKFZ* ; Chintharlapalli, S. ; Augustin, H. (Last author)DKFZ*

2021
Philadelphia, Pa.

This record in other databases:  

Please use a persistent id in citations: doi:10.1158/2159-8290.CD-20-0122

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 GEMM fragment-based tumor model uniquely sustaining a functional network of intratumoral lymphatics that facilitates seeding of fatal peripheral metastases. Multi-regimen 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 pre-surgical Ang2-neutralization was sufficient to prolong survival by regressing established intratumoral lymphatics, hence identifying a novel therapeutic regimen that warrants further clinical evaluation.

Note: DKFZ-ZMBH Alliance#EA:A190#LA:A190#2021 Feb;11(2):424-445

---

Contributing Institute(s):

1. A190 Vaskuläre Onkologie und Metastasierung (A190)
2. Bioinformatik und Omics Data Analytics (B240)
3. Molekulare Grundlagen Gastrointestinaler Tumoren (D200)
4. KKE Dermatoonkologie (A370)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2021

---

Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Essential Science Indicators ; IF >= 25 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---