Understanding the effect of mechanical forces on ovarian cancer progression.

OBJECTIVE: Mechanical forces including tension, compression, and shear stress are increasingly implicated in tumor progression and metastasis. Understanding the mechanisms behind epithelial ovarian cancer (EOC) progression and metastasis is critical, and this study aimed to elucidate the effect of oscillatory and constant tension on EOC. METHODS: SKOV-3 and OVCAR-8 EOC cell lines were placed under oscillatory tension for 3 days and compared to cells placed under no tension. Cell proliferation, migration, and invasion were analyzed while RNAseq and Western Blots helped investigate the biological mechanisms underlying the increasingly aggressive state of the experimental cells. Finally, in vivo experiments using SCID mice assisted in confirming the in vitro results. RESULTS: Oscillatory tension (OT) and constant tension (CT) significantly increased SKOV-3 proliferation, while OT caused a significant increase in proliferative genes, migration, and invasion in this cell line. CT did not cause significant increases in these areas. Neither OT nor CT increased proliferation or invasion in OVCAR-8 cells, while both tension types significantly increased cellular migration. Two proteins involved in metastasis, E-cadherin and Snail, were both significantly affected by OT in both cell lines, with E-cadherin levels decreasing and Snail levels increasing. In vivo, tumor growth and weight for both cell types were significantly increased, and ascites development was significantly higher in the experimental OVCAR-8 group than in the control group. CONCLUSIONS: This study found that mechanical forces are influential in EOC progression and metastasis. Further analysis of downstream mechanisms involved in EOC metastasis will be critical for improvements in EOC treatment.

Manipulating the Wnt/ß-catenin signaling pathway to promote anti-tumor immune infiltration into the TME to sensitize ovarian cancer to ICB therapy.

OBJECTIVE: Immune checkpoint blockade (ICB) therapy shows limited efficacy in ovarian cancers due to the "cold" immune phenotype surrounding these tumors. Previous studies have shown that in ovarian cancer Wnt/ß-catenin pathway activation contributes to this immune phenotype. Here, we evaluated the anti-tumor and immune-enhancing properties of the Wnt inhibitor, CGX-1321, used alone or in combination with either DKN-01 or anti-PD-1 therapy, in pre-clinical ovarian cancer models. METHODS: The parental ID8 murine ovarian cancer model harboring a knock-out of p53 (ID8p53-/-) and MISIIR-Tag spontaneous ovarian cancer models were used to test the effects of CGX-1321 alone or in combination therapies on tumor burden and immune cell landscape in the tumor microenvironment (TME). Flow cytometry and NanoString analyses were used to characterize the changes in tumor-intrinsic signaling and immune-related profiles in the TME of ovarian cancer in response to treatments. RESULTS: CGX-1321 significantly reduced tumor burden and constrained tumor progression in the ID8p53-/- and MISIIR-Tag models. Furthermore, CGX-1321 increased infiltrating CD8+ T cells in the TME. Combining CGX-1321 with either DKN-01 or anti-PD-1 therapy also decreased tumor burden and increased CD8+ T cell infiltration in the omentum TME but did not do so to a greater extent that CGX-1321 monotherapy. CONCLUSIONS: CGX-1321 significantly reduced tumor burden and enhanced CD8+ T cell levels in ovarian cancer, nevertheless the addition of DKN-01 or anti-PD-1 therapies did not enhance these effects of CGX-1321. Further investigation is needed to determine if CGX-1321 + DKN-01 combination treatment sensitizes pre-clinical ovarian cancer to ICB therapy.

Response to anti-DKK1 therapy in uterine carcinosarcoma: A case report.

Targeted therapies are being increasingly used in clinical practice and trials. However, tumor heterogeneity among sites of metastatic disease can occur creating a conundrum when utilizing biomarker directed therapies. Here we demonstrate a patient with recurrent uterine carcinosarcoma whose local recurrence and metastatic recurrence had a varied response to paclitaxel in combination with DKN-01, a monoclonal antibody against DKK1, a modulator of Wnt/ß-catenin and PI3K/AKT signaling pathways. This may be explained by differences in mutational profile found between the two sites. Our findings highlight the importance of analyzing tissue from the primary tumor as well as metastatic lesions, especially if there is a discrepancy in their response to treatment.