SUMMARY Ovarian cancer has a clear predilection for metastasis to the omentum, but the underlying mechanisms involved in ovarian cancer spread are not well understood. Here, we used a parabiosis model that demonstrates preferential hematogenous metastasis of ovarian cancer to the omentum. Our studies revealed that the ErbB3-neuregulin1 (NRG1) axis is a dominant pathway responsible for hematogenous omental metastasis. Elevated levels of ErbB3 in ovarian cancer cells and NRG1 in the omentum allowed for tumor cell localization and growth in the omentum. Depletion of ErbB3 in ovarian cancer impaired omental metastasis. Our results highlight hematogenous metastasis as an important mode of ovarian cancer metastasis. These findings have implications for designing alternative strategies aimed at preventing and treating ovarian cancer metastasis.

SUMMARY 3q26.2 amplification in high-grade serous ovarian cancer leads to increased expression of mature microRNA miR551b-3p, which is associated with poor clinical outcome. Importantly, miR551b-3p contributes to resistance to apoptosis and increased survival and proliferation of cancer cells in vitro and in vivo. miR551b-3p up-regulates STAT3 protein levels with STAT3 being required for the effects of miR551b-3p on cell proliferation. Rather than decreasing levels of target mRNA as expected, we demonstrate that miR551b-3p binds a complementary sequence on the STAT3 promoter recruiting RNA Polymerase II and the TWIST1 transcription factor to activate STAT3 transcription and thus directly upregulates STAT3 expression. Furthermore, anti-miR551b reduced STAT3 expression in ovarian cancer cells in vitro and in vivo and reduced ovarian cancer growth in vivo. Together our data demonstrates a role for miR551b-3p in transcriptional activation. Thus miR551b-3p represents a promising candidate biomarker and therapeutic target in ovarian cancer.

Highlights d miR551b-3p translocates to the nucleus and activates STAT3 transcription d Importin-8 (IPO8) is required for the nuclear translocation of miR551b-3p d miR551b-3p activates the expression of OSM family genes for autocrine signaling loop d Inhibition of miR551b-3p disrupts OSM-mediated signaling addiction

SUMMARY Small noncoding miRNAs represent underexplored targets of genomic aberrations and emerging therapeutic targets. The 3q26.2 amplicon is among the most frequent genomic aberrations in multiple cancer lineages including ovarian and breast cancers. We demonstrate that hsa-miR-569 (hereafter designated as miR569), which is overexpressed in a subset of ovarian and breast cancers, at least in part due to the 3q26.2 amplicon, alters cell survival and proliferation. Downregulation of TP53INP1 expression by miR569 is required for the effects of miR569 on survival and proliferation. Targeting miR569 sensitizes ovarian and breast cancer cells overexpressing miR569 to cisplatin by increasing cell death both in vitro and in vivo. Thus targeting miR569 could potentially benefit patients with the 3q26.2 amplicon and subsequent miR569 elevation.

Metastatic outcomes depend on the interactions of metastatic cells with a specific organ microenvironment. Our previous studies have shown that triple-negative breast cancer (TNBC) MDA-MB-231 cells passaged in astrocyte-conditioned medium (ACM) show proclivity to form brain metastases, but the underlying mechanism is unknown. The combination of microarray analysis, qPCR, and ELISA assay were carried out to demonstrate the ACM-induced expression of angiopoietin-like 4 (ANGPTL4) in TNBC cells. A stable ANGPTL4-knockdown MDA-MB-231 cell line was generated by ANGPTL4 short-hairpin RNA (shRNA) and inoculated into mice via left ventricular injection to evaluate the role of ANGPTL4 in brain metastasis formation. The approaches of siRNA, neutralizing antibodies, inhibitors, and immunoprecipitation were used to demonstrate the involved signaling molecules. We first found that ACM-conditioned TNBC cells upregulated the expression of ANGPTL4, a secreted glycoprotein whose effect on tumor progression is known to be tumor microenvironment- and tumor-type dependent. Knockdown of ANGPTL4 in TNBC MDA-MB-231 cells with shRNA decreased ACM-induced tumor cell metastatic growth in the brain and attributed to survival in a mouse model. Furthermore, we identified that astrocytes produced transforming growth factor-beta 2 (TGF-β2), which in part is responsible for upregulation of ANGPTL4 expression in TNBC through induction of SMAD signaling. Moreover, we identified that tumor cells communicate with astrocytes, where tumor cell-derived interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) increased the expression of TGF-β2 in astrocytes. Collectively, these findings indicate that the invading TNBC cells interact with astrocytes in the brain microenvironment that facilitates brain metastases of TNBC cells through a TGF-β2/ANGPTL4 axis. This provides groundwork to target ANGPTL4 as a treatment for breast cancer brain metastases.

High-grade serous carcinoma, accounts for up to 70% of all ovarian cases. Furin, a proprotein convertase, is highly expressed in high-grade serous carcinoma of ovarian cancer patients, and its expression is even higher in tumor omentum than in normal omentum, the preferred site of ovarian cancer metastasis. The proteolytic actions of this cellular endoprotease helps the maturation of several important precursors of protein substrates and its levels increase the risk of several cancer. We show that furin activates the IGF1R/STAT3 signaling axis in ovarian cancer cells. Conversely, furin knockdown downregulated IGF1R-β and p-STAT3 (Tyr705) expression. Further, silencing furin reduced tumor cell migration and invasion in vitro and tumor growth and metastasis in vivo . Collectively, our findings show that furin can be an effective therapeutic target for ovarian cancer prevention or treatment.

The development of effective therapies for cancer treatment requires a better understanding of the tumor extracellular environment and a dynamic interaction between tumor cells, the cells of the immune system, and the tumor stroma. Increasing evidence suggests that extracellular vesicles play an important role in this interaction. Extracellular vesicles are nanometer-sized membrane-bound vesicles secreted by various types of cells that facilitate intracellular communication by transferring proteins, various lipids, and nucleic acids, especially miRNAs, between cells. Extracellular vesicles play discrete roles in the immune regulatory functions, such as antigen presentation, and activation or suppression of immune cells. Achieving therapeutic intervention through targeting of extracellular vesicles is a crucial area of research now. Thus, a deeper knowledge of exosome biology and the molecular mechanism of immune regulation is likely to provide significant insight into therapeutic intervention utilizing extracellular vesicles to combat this dreadful disease. This review describes the recent updates on immune regulation by extracellular vesicles in cancer progression and possible use in cancer therapy.

SUMMARY Fragile X-related protein-1 (FXR1) gene is highly amplified in patients with ovarian cancer, and this amplification is associated with increased expression of both FXR1 mRNA and protein. FXR1 expression directly associates with the survival and proliferation of cancer cells. Surface sensing of translation (SUnSET) assay demonstrates that FXR1 enhances the overall translation in cancer cells. Reverse-phase protein array (RPPA) reveals that cMYC is the key target of FXR1. Mechanistically, FXR1 binds to the AU-rich elements (ARE) present within the 3′ untranslated region (3′UTR) of cMYC and stabilizes its expression. In addition, the RGG domain in FXR1 interacts with eIF4A1 and eIF4E proteins. These two interactions of FXR1 result in the circularization of cMYC mRNA and facilitate the recruitment of eukaryotic translation initiation factors to the translation start site. In brief, we uncover a mechanism by which FXR1 promotes cMYC levels in cancer cells.