TY - JOUR
T1 - Signals from the metastatic niche regulate early and advanced ovarian cancer metastasis through miR-4454 downregulation
AU - Dasari, Subramanyam
AU - Pandhiri, Taruni
AU - Grassi, Tommaso
AU - Visscher, Daniel W.
AU - Multinu, Francesco
AU - Agarwal, Komal
AU - Mariani, Andrea
AU - Shridhar, Viji
AU - Mitra, Anirban K.
N1 - Funding Information:
We are deeply indebted to the patients for their generosity and thankful to Dr. Xiongbin Lu for critically reviewing the manuscript. We also acknowledge the help of the Center for Genomics and Bioinformatics and Flow Cytometry Core Facility at IU Bloomington as well as the Immunohistochemistry Core of IUSM. This research was supported by DoD OCRP Ovarian Cancer Academy Award (W81XWH-15-0253), Colleen's Dream Foundation, CTSI Core Pilot and Ralph W. and Grace M. Showalter Research Awards. The tumor collection and miRNAseq was supported in part by grants from the NIH (P50CA136393 and R01-CA133443), Andersen Foundation (to A.K. Mitra), the Department
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1541-7786.MCR-19-1162
DO - 10.1158/1541-7786.MCR-19-1162
M3 - Article
C2 - 32350057
AN - SCOPUS:85089165046
SN - 1541-7786
VL - 18
SP - 1202
EP - 1217
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 8
ER -