Abstract A30: Frizzled-7 (FZD7)-mediated non-canonical Wnt-Planar Cell Polarity (PCP) signalling pathway as a novel molecular driver for the C5/Proliferative/Stem-A molecular subtype of ovarian cancer.
Asad, M; Wong, MK; Tan, TZ; Virshup, D; Thiery, JP; Huang, RY-J
Published in: Clinical Cancer Research
Ovarian cancer (OC), in particular high grade serous carcinoma (HGSC), has been shown to exhibit diverse molecular heterogeneity based on gene expression profiling by the Australian and the TCGA cohorts. This molecular heterogeneity has been demonstrated to be very robust and reproducible by a large-scale meta-analysis study consisting of 1,538 samples from our group. At least 5 distinct gene-expression based molecular subtypes (GEMS) of EOC have been identified. The C5 subtype from the Tothill dataset corresponds to the Proliferative subtype from the TCGA dataset and the Stem-A subtype from the 1,538 meta-analysis dataset. These GEMS have been correlated with patient survival. The C5/Proliferative/Stem-A GEMS is associated with poorer survival outcomes. From our own study, Stem-A OC cells tend to display preferential chemosensitivity towards microtubule depolymerizing agents affecting the plus-end dynamics of microtubule such as vincristine and vinorelbine. Interestingly, Stem-A as well as non-Stem-A cells are equally sensitive to microtubule stabilizing agents such as paclitaxel. The biology of this C5/Proliferative/Stem-A-subtyped OC is still elusive and requires in-depth study. Here, we demonstrate that a Wnt receptor Frizzled-7 (FZD7) is crucial for the aggressiveness of the C5/Proliferative/Stem-A GEMS. Silencing FZD7 in the Stem-A-subtyped OC induces decrease in cell proliferation and cell cycle arrest. Silencing FZD7 also induced compaction of OC cell colony and strengthening of actin cytoskeleton at cell-cell junctions. Stable FZD7 knockdown clones further demonstrate significant decrease in anoikis resistance, spheroid forming ability, and tumorigenesis in xenografts. We further show that these functional changes acts via the Wnt-planar cell polarity (PCP) pathway downstream of FZD7. A subset of PCP pathway genes is also enriched in Stem-A tumors. Transient silencing of three downstream PCP pathway genes, CELSR3, PRICKLE4, PTK7, gave rise to similar functional phenotypes as silencing FZD7. These FZD7-PCP silenced Stem-A OC cells also demonstrate enhanced sensitivity to the microtubule depolymerizing agent vinorelbine. We conclude that the FZD7-PCP pathway drives the aggressiveness of the C5/Proliferative/Stem-A-subtyped OC and can be potentially utilized as the marker to identify the Stem-A subgroup. Molecularly stratifying OC patients and targeting C5/Proliferative/Stem-A subtype with therapeutics against FZD7-PCP pathway would be a novel strategy for OC.Citation Format: Mohammad Asad, Meng Kang Wong, Tuan Zea Tan, David Virshup, Jean Paul Thiery, Ruby Yun-Ju Huang. Frizzled-7 (FZD7)-mediated non-canonical Wnt-Planar Cell Polarity (PCP) signalling pathway as a novel molecular driver for the C5/Proliferative/Stem-A molecular subtype of ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A30.
