Regulation of the bi-directional cross-talk between ovarian cancer cells and adipocytes by SPARC

• Published in: Oncogene 2019-05, Vol.38 (22), p.4366-4383
• Main Authors: John, Bincy, Naczki, Christine, Patel, Chirayu, Ghoneum, Alia, Qasem, Shadi, Salih, Ziyan, Said, Neveen
• Format: Article
• Language: English
• Subjects: 13/105; 13/106; 13/109; 13/21; 14/19; 14/28; 14/63; 38/109; 38/77; 631/1647/334; 631/67/1517/1709; 64/110; 82/80; Activator protein 1; Adipocytes; Adipocytes - metabolism; Adipocytes - pathology; Animals; Apoptosis; Cancer cells; Cancer metastasis; Cancer research; Cell Biology; Cell Differentiation - physiology; Cell interactions; Cell Line, Tumor; Cell proliferation; Cell Proliferation - physiology; Coculture Techniques - methods; Colonization; Cysteine; Cystine; Female; Gene expression; Genetic aspects; Genetic engineering; Genetically modified organisms; Human Genetics; Humans; Internal Medicine; Machinery; Medicine; Medicine & Public Health; Metastases; Metastasis; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasm Invasiveness - pathology; NF-κB protein; Novels; Omentum; Omentum - metabolism; Omentum - pathology; Oncology; Osteonectin; Osteonectin - metabolism; Ovarian cancer; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Ovary - metabolism; Ovary - pathology; Peritoneum; Phenotypes; Proteins; Rodents; Transcription factors; Transcription, Genetic - physiology; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-019-0728-3

Ovarian cancer (OvCa) exhibits a specific predilection for metastasis to the omentum. Our earlier studies highlighted the tumour-suppressor effect of secreted protein acidic and rich in cysteine (SPARC) in OvCa through multi-faceted roles inhibiting cancer cell interactions within the peritoneal milieu. The goal of this study is to investigate the role of SPARC in OvCa interactions with omental adipocytes and its role in OvCa colonization in the omentum. We employed multi-pronged approach using primary omental adipocytes from Sparc knockout mice, genetically engineered human omental adipocytes in 3D co-cultures with OvCa cells, as well as treatment with recombinant SPARC protein. We show that SPARC suppresses multistep cascade in OvCa omental metastasis. SPARC inhibited in vivo and adipocyte-induced homing, proliferation, and invasion of OvCa cells. SPARC suppressed metabolic programming of both adipocytes and OvCa cells and exerted an inhibitory effect of adipocyte differentiation and their phenotypic switch to cancer-associated phenotype. Mechanistic studies revealed that this effect is mediated through inhibition of cEBPβ-NFkB-AP-1 transcription machinery. These findings define a novel and functionally important role of SPARC in OvCa and not only bridge the knowledge gap but highlight the need to consider SPARC protein expression in therapeutic development.