☆ 4.8 Article

Tumor Cell-Derived Angiopoietin-2 Promotes Metastasis in Melanoma

CANCER RESEARCH (2020)

Journal

CANCER RESEARCH

Volume 80, Issue 12, Pages 2586-2598

Publisher

AMER ASSOC CANCER RESEARCH

DOI: 10.1158/0008-5472.CAN-19-2660

Keywords

Funding

Deutsche Forschungsgemeinschaft [248813719]
DFG [259332240, CRC-TR209]
European Research Council Advanced Grant AngioMature [787181]
European Research Council (ERC) [787181] Funding Source: European Research Council (ERC)

Ask authors/readers for more resources

Protocol

Community support

Reagent

Community support

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 cellderived ANGPT2 augments metastatic colonization by protecting tumor cells from oxidative stress.

Authors

I am an author on this paper

Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.8

Not enough ratings

Secondary Ratings

Novelty

Significance

Scientific rigor

Rate this paper

TIE-2 Signaling Activation by Angiopoietin 2 On Myeloid-Derived Suppressor Cells Promotes Melanoma-Specific T-cell Inhibition

Amelie Marguier, Caroline Laheurte, Benoit Lecoester, Marine Malfroy, Laura Boullerot, Adeline Renaudin, Evan Seffar, Abhishek Kumar, Charlee Nardin, Francois Aubin, Olivier Adotevi

Summary: This study investigates a novel subset of monocytic MDSCs called TIE-2(+) M-MDSCs in melanoma patients. These cells show a highly immunosuppressive phenotype and are associated with the pro-angiogenic factor ANGPT2. The study demonstrates that exposure to ANGPT2 increases the immune suppressive function of TIE-2(+) M-MDSCs and that active TIE-2 signaling is required for optimal suppressive activity. This suggests that the TIE-2(+) M-MDSC/ANGPT2 axis may play a role in immune escape in melanoma.

FRONTIERS IN IMMUNOLOGY (2022)