GATA3 as a master regulator for interactions of tumor-associated macrophages with high-grade serous ovarian carcinoma
Authors: Mohammed Rashed
Anil K Sood
Salama Abdou Salama
Recep Bayraktar
Bulent Ozpolat
Cristina Ivan
Amr Ahmed El-Arabey
Gabriel Lopez-Berestein
Adel Rashad Abd-Allah
Merve Denizli
Pinar Kanlikilicer
George A Calin
Nashwa Kabil
Journal: Cellular signalling (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: GATA3; High-grade serous ovarian carcinoma; M2 macrophages; Ovarian cancer; TP53
Affiliations: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Pharmacology and Toxicology, Al-Azhar University, Faculty of Pharmacy, Cairo, Egypt., Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Pharmacology and Toxicology, Al-Azhar University, Faculty of Pharmacy, Cairo, Egypt., Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: .

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 &lt; .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. 

Retracted: No

PubPeer comments:
 Are the 2 marked macrophages in Figure 2E intended to be the same? Features appear quite similar. ***   , 
 Correction, January 2022: https: www.sciencedirect.com science article pii S0898656821002369  *The authors apologize for the error in Fig. 2E- The Figure legend should have made it clear that M0 macrophages: the top panel was a low magnification and the mid panel was a higher magnification of the same cell. There was no intent of duplication.* Fig. 2 corrected legend.  *Fig. 2 Macrophage and exosome characterization. (A) Morphology of undifferentiated monocytes at day 0, showing a cell diameter of 30u202fu03bcm under 3D atomic force microscopy (AFM). (B) Morphology of M0 macrophages after 3u202fdays of treatment, showing a cell diameter of 30u202fu03bcm under 3D AFM. (C) Morphology of M2 macrophages after 24u202fh of treatment with IL-4 and IL-13, showing a cell diameter of 100u202fu03bcm under 3D AFM. (D, E) Characteristic morphology of M2 macrophages compared with M0 macrophages: cell elongation to modulate macrophage phenotype polarization (AFM and 3D optical microscopy); E) M0 macrophages: top panel- low magnification and mid panel- higher magnification of the same cell (F) Immunoblotting to validate the macrophage markers CD206, CD68, and CD163 in differentiated THP-1 cells and undifferentiated THP-1 cells. (G) Flow cytometry analysis to verify differential expression of M2 markers CD163 and CD206 between differentiated and undifferentiated THP-1 cells (Pu202f u202f.05). (H) Quantification of isolated exosomes from tumor-associated macrophages (Nano sight).* ,