Journal Article

DKFZ-2020-00852

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Tumor cell-derived Angiopoietin-2 promotes metastasis in melanoma.

Abdul Pari, A. A. (First author)DKFZ* ; Singhal, M. (First author)DKFZ* ; Hübers, C.DKFZ* ; Mogler, C. ; Schieb, B.DKFZ* ; Gampp, A.DKFZ* ; Gengenbacher, N.DKFZ* ; Reynolds, L. E. ; Terhardt, D.DKFZ* ; Géraud, C. ; Utikal, J.DKFZ* ; Thomas, M. ; Goerdt, S. ; Hodivala-Dilke, K. M. ; Augustin, H. (Last author)DKFZ* ; Felcht, M.Extern*

2020
AACR Philadelphia, Pa.

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Please use a persistent id in citations: doi:10.1158/0008-5472.CAN-19-2660

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 pathological disorders like inflammation and cancer. However, scattered reports have also portrayed tumor cells as a source of ANGPT2. Employing in situ hybridization-based detection of ANGPT2, we found strong tumor cell expression of ANGPT2 in a subset of melanoma patients. 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 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 melanoma patients.

Note: DKFZ-ZMBH Alliance2020 Jun 15;80(12):2586-2598#EA:A190#LA:A190#

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Contributing Institute(s):

1. A190 Vaskuläre Onkologie und Metastatistierung (A190)
2. KKE Dermatoonkologie (A370)
3. DKTK HD zentral (HD01)

Research Program(s):

1. 311 - Signalling pathways, cell and tumor biology (POF3-311) (POF3-311)

Appears in the scientific report 2020

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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