Browsing by Author "Agarwal, Komal"

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    Productive Cross-Talk with the Microenvironment: A Critical Step in Ovarian Cancer Metastasis
    (MDPI, 2019-10-21) Abd El Aziz, Mohamed A.; Agarwal, Komal; Dasari, Subramanyam; Mitra, Anirban K.; Medical and Molecular Genetics, School of Medicine
    Most ovarian cancer patients present with disseminated disease at the time of their diagnosis, which is one of the main reasons for their poor prognosis. Metastasis is a multi-step process and a clear understanding of the mechanism of regulation of these steps remains elusive. Productive reciprocal interactions between the metastasizing ovarian cancer cells and the microenvironment of the metastatic site or the tumor microenvironment play an important role in the successful establishment of metastasis. Much progress has been made in the recent past in our understanding of such interactions and the role of the cellular and acellular components of the microenvironment in establishing the metastatic tumors. This review will outline the role of the microenvironmental components of the ovarian cancer metastatic niche and their role in helping establish the metastatic tumors. Special emphasis will be given to the mesothelial cells, which are the first cells encountered by the cancer cells at the site of metastasis.
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    Signals from the Metastatic Niche Regulate Early and Advanced Ovarian Cancer Metastasis through miR-4454 Downregulation
    (AACR, 2020-08) Dasari, Subramanyam; Pandhiri, Taruni; Grassi, Tommaso; Visscher, Daniel W.; Multinu, Francesco; Agarwal, Komal; Mariani, Andrea; Shridhar, Viji; Mitra, Anirban K.; Medical and Molecular Genetics, School of Medicine
    Treatment of ovarian cancer is limited by extensive metastasis and yet it remains poorly understood. We have studied the critical step of metastatic colonization in the context of the productive interactions with the metastatic microenvironment with a goal of identifying key regulators. By combining miRNA expression analysis using an organotypic 3D culture model of early ovarian cancer metastasis with that of matched primary and metastatic tumors from 42 patients with ovarian cancer, we identified miR-4454 as a key regulator of both early colonization and advanced metastasis in patients with ovarian cancer. miR-4454 was downregulated in the metastasizing ovarian cancer cells through paracrine signals from microenvironmental fibroblasts, which promoted migration, invasion, proliferation, and clonogenic growth in ovarian cancer cells as well as their ability to penetrate through the outer layers of the omentum. Stable overexpression of miR-4454 decreased metastasis in ovarian cancer xenografts. Its mechanism of action was through the upregulation of its targets, secreted protein acidic and cysteine rich (SPARC) and BCL2 associated athanogene 5 (BAG5), which activated focal adhesion kinase (FAK) signaling, promoted mutant p53 gain of function by its stabilization, and inhibited apoptosis. Because microenvironment-induced downregulation of miR-4454 is essential for early and advanced metastasis, targeting it could be a promising therapeutic approach.