Noncanonical IL6 Signaling-Mediated Activation of YAP Regulates Cell Migration and Invasion in Ovarian Clear Cell Cancer.

Abstract

Ovarian clear cell adenocarcinoma (OCCA) is characterized by a particularly poor response to conventional chemotherapy and a short overall survival time in women with established disease. The development of targeted treatments for OCCA relies on a better understanding of its molecular characteristics. IL6 is strongly expressed in OCCA and may therefore provide a novel therapeutic target. Here we use CRISPR/Cas9 and conditional short hairpin interfering RNA to perform loss-of-function studies in human OCCA cell lines to explore the requirement for IL6 in vitro and in vivo. While reduction of IL6 expression exerted limited effects in vitro, its attenuation significantly impaired tumor growth and neovascularization in vivo. In contrast to typical signaling via STAT3, IL6 in OCCA signaled via a noncanonical pathway involving gp130, Src, and the Hippo pathway protein YAP. A high-throughput combination drug screen identified agents that enhanced cell killing following reduction of IL6 signaling. Intersection of screen hits obtained from two cell lines and orthogonal approaches to attenuation of IL6 yielded AKT and EGFR inhibitors as enhancers of the inhibitory monoclonal IL6 receptor antibody tocilizumab. This study defines for the first time the requirements for, and mechanisms of, signaling by IL6 in human OCCA cell lines and identifies potential combinatory therapeutic approaches. Given the molecular diversity of OCCA, further in vitro and in vivo studies are warranted to determine whether such approaches will overcome the limited efficacy of tocilizumab observed in ovarian cancer to date. SIGNIFICANCE: This study defines the requirements for and mechanisms of noncanonical signaling by IL6 in human ovarian clear cell adenocarcinoma cell lines and identifies combinatory therapeutic approaches to be explored clinically.

• Authors: Walid J Azar, Elizabeth L Christie, Chris Mitchell, David S Liu, George Au-Yeung, David D L Bowtell
• Journal: Cancer research (Cancer Res) Vol. 80 Issue 22 Pg. 4960-4971 (11 15 2020) ISSN: 1538-7445 [Electronic] United States
• PMID: 32917727 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Adaptor Proteins, Signal Transducing
• Antibodies, Monoclonal, Humanized
• Interleukin-6
• Neoplasm Proteins
• STAT3 Transcription Factor
• STAT3 protein, human
• Transcription Factors
• YAP-Signaling Proteins
• YAP1 protein, human
• tocilizumab

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Adenocarcinoma, Clear Cell (drug therapy, metabolism, pathology)
• Animals
• Antibodies, Monoclonal, Humanized (pharmacology)
• Cell Movement (physiology)
• Clustered Regularly Interspaced Short Palindromic Repeats
• Female
• Gene Expression Profiling
• Heterografts
• Humans
• Interleukin-6 (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Invasiveness
• Neoplasm Proteins (metabolism)
• Oligonucleotide Array Sequence Analysis
• Ovarian Neoplasms (drug therapy, metabolism, pathology)
• STAT3 Transcription Factor (metabolism)
• Transcription Factors (metabolism)
• YAP-Signaling Proteins