GATA3 as a master regulator for interactions of tumor-associated macrophages with high-grade serous ovarian carcinoma

Amr Ahmed El-Arabey, Merve Denizli, Pinar Kanlikilicer, Recep Bayraktar, Cristina Ivan, Mohammed Rashed, Nashwa Kabil, Bulent Ozpolat, George A. Calin, Salama Abdu Salama, Adel Rashad Abd-Allah, Anil K. Sood, Gabriel Lopez-Berestein

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic cancer. Emerging evidence suggests that tumor-associated macrophages (TAMs) play an immunosuppressive role in the tumor microenvironment and promote tumor growth, angiogenesis, and metastasis in ovarian cancer. Therefore, targeting TAMs in patients with ovarian cancer is an appealing strategy; however, all trials to date have failed. To improve the efficacy of this approach, we sought to elucidate the underlying mechanisms of the role of TAMs in ovarian cancer. We found that the developmental transcription factor GATA3 was highly expressed in HGSOC cell lines but not in the fallopian tube, which is the main origin of HGSOC. GATA3 expression was associated with poor prognosis in HGSOC patients (P < .05) and was found to promote proliferation and migration in HGSOC cell lines. GATA3 was released abundantly from TAM cells via exosomes and contributed to tumor growth in the tumor microenvironment. Moreover, GATA3 acted as a regulator for macrophage polarization and interactions between TAMs and HGSOC to support proliferation, motility, and cisplatin chemoresistance in mutant TP53 HGSOC cell lines. Furthermore, GATA3 played a critical role in the interactions between TAMs and mutant TP53 HGSOC to promote angiogenesis and epithelial-mesenchymal transition with epigenetic regulation. Targeting GATA3 using GATA3siRNA in TAMs impeded GATA3-driven proliferation, migration, cisplatin chemoresistance, and angiogenesis in mutant TP53 HGSOC cell lines. Our findings indicate that GATA3 plays a novel role in immunoediting of HGSOC and demonstrate that GATA3 may serve as a prognostic marker for HGSOC and a promising target in the treatment of HGSOC.

Original languageEnglish (US)
Article number109539
JournalCellular Signalling
Volume68
DOIs
StatePublished - Apr 2020

Keywords

  • GATA3
  • High-grade serous ovarian carcinoma
  • M2 macrophages
  • Ovarian cancer
  • TP53
  • Tumor-associated macrophages

ASJC Scopus subject areas

  • Cell Biology

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