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Background: Platinum-based chemotherapy regimens are a mainstay in the management of ovarian cancer (OC), but emergence of chemoresistance poses a significant clinical challenge. The persistence of ovarian cancer stem cells (OCSCs) at the end of primary treatment contributes to disease recurrence. Here, we hypothesized that the extracellular matrix protects CSCs during chemotherapy and supports their tumorigenic functions by activating integrin-linked kinase (ILK), a key enzyme in drug resistance. Methods: TCGA datasets and OC models were investigated using an integrated proteomic and gene expression analysis and examined ILK for correlations with chemoresistance pathways and clinical outcomes. Canonical Wnt pathway components, pro-survival signaling, and stemness were examined using OC models. To investigate the role of ILK in the OCSC-phenotype, a novel pharmacological inhibitor of ILK in combination with carboplatin was utilized in vitro and in vivo OC models. Results: In response to increased fibronectin secretion and integrin β1 clustering, aberrant ILK activation supported the OCSC phenotype, contributing to OC spheroid proliferation and reduced response to platinum treatment. Complexes formed by ILK with the Wnt receptor frizzled 7 (Fzd7) were detected in tumors and correlated with metastatic progression. Moreover, TCGA datasets confirmed that combined expression of ILK and Fzd7 in high grade serous ovarian tumors is correlated with reduced response to chemotherapy and poor patient outcomes. Mechanistically, interaction of ILK with Fzd7 increased the response to Wnt ligands, thereby amplifying the stemness-associated Wnt/β-catenin signaling. Notably, preclinical studies showed that the novel ILK inhibitor compound 22 (cpd-22) alone disrupted ILK interaction with Fzd7 and CSC proliferation as spheroids. Furthermore, when combined with carboplatin, this disruption led to sustained AKT inhibition, apoptotic damage in OCSCs and reduced tumorigenicity in mice. Conclusions: This "outside-in" signaling mechanism is potentially actionable, and combined targeting of ILK-Fzd7 may lead to new therapeutic approaches to eradicate OCSCs and improve patient outcomes. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Integrin-linked kinase-frizzled 7 interaction maintains cancer stem cells to drive platinum resistance in ovarian cancer." The correction states that Rula Atwani and Rohit Pravin Nagare are co-first authors of the article. It also acknowledges an error in the author name of Rohit Pravin Nagare, which has been corrected. The publisher, Springer Nature, maintains neutrality regarding jurisdictional claims and institutional affiliations. The authors of the article are Rula Atwani, Rohit Pravin Nagare, Amber Rogers, Mayuri Prasad, Virginie Lazar, George Sandusky, Yan Tong, Fabrizio Pin, and Salvatore Condello. [Extracted from the article]

BACKGROUND: There has been variability between laboratories in the identification of cancer stem cells (CSCs) markers for epithelial ovarian cancer (EOC). We have evaluated three new surface markers for EOC to identify CSCs precisely. METHODS: Three new putative CSCs specific surface markers CD9, CD24 and EPHA1 identified by a bioinformatics approach were evaluated in normal ovary, fallopian tube and ovarian tumours. RESULTS: The expression of CD9 alone was observed in normal ovarian surface epithelium and fallopian tube whereas CD24 and EPHA1 were not expressed (n = 5). CD24 was expressed in all tumours (N = 101) while CD9 and EPHA1 were expressed in 89 and 71 tumours, respectively. The statistical analysis showed significant correlation of the stage of the disease (p < 0.0001), type of surgery (p < 0.0001) and residual disease (p < 0.0001) with overall survival. Although expression of CD9, CD24 and EPHA1 was observed in the majority of tumours there was no significant correlation with outcome. In patients who underwent primary surgery, increased expression of CD24 significantly correlated with poor survival. The expression of CD24 was significantly reduced (p < 0.002) upon analysis of paired sections from patients prior to surgery and at interval debulking surgery (n = 16). CONCLUSION: These findings suggest that overexpression of these new markers may be useful in identifying and targeting ovarian CSCs and CD24 may be a putative CSCs marker in ovarian cancer. [ABSTRACT FROM AUTHOR]

SIGNALING THROUGH THE HEDGEHOG PATHWAY IN OVARIAN CANCER Sneha S, Nagare R. P, Krishna Priya S and Ganesan TS. Departments of Medical Oncology & Clinical Research, Cancer Institute (WIA), Chennai tsganesan@gmail.com Background: The signaling pathways that cancer stem cells (CSCs) employ may be similar to those in embryonic stem cells. These are 'wnt', 'notch' and 'hedgehog'. Objective: Evaluate signaling by CSCs, using specific small molecule inhibitors in serous ovarian cancer cells. Methods: Serous ovarian cancer cell lines (N=7) were cultured as spheroids under stem cell conditions in the presence or absence of small molecule inhibitors and counted after two weeks. The effect on cell proliferation was evaluated by the MTT assay. In addition, cells from malignant ascites from patients with serous adenocarcinoma of the ovary (PMC) were cultured as monolayer in the presence or absence of inhibitors. Assays were performed to analyse effect on CSCs. These were ALDH1A1 assay (N=20), Hoechst exclusion assay (N=3), expression of surface markers (N=20), wound healing assay (N=6), and colony assay (N=7). The effect on the cell cycle of CSCs was analysed using Hoechst and Pyronin Y. Results: Spheroid formation in OVCAR3 and UC1101 cells was inhibited completely by the smoothened inhibitor (SMO) GDC0449 (3 μM) despite lack of cytotoxic effect when evaluated by the MTT assay. Flow cytometry analysis of PMC cultured in the presence of GDC0449 showed significant reduction in the expression of ALDH1A1 (2.5±0.9), CD44 (18.6±5.5), CD9 (1.6±0.8), CD133 (0.5±0.3), CD117 (18.8±13.4), CD24 (0.1±0). Similar results were obtained with inhibitors, LDE225 (SMO, 2.5nM) and GANT61 (Gli, 5 μM). Significant reduction in migration of PMC was observed in the scratch assay and clonogenic assay in the presence of inhibitors (P< 0.001). Side population assay revealed a reduction in CSCs following treatment with GANT61 (P< 0.05). In PMC, GANT61 also decreased the quiescent (Hoechst33342low/PyroninYlow) cell population (P< 0.05). Discussion and Conclusion: These results demonstrate that the hedgehog pathway is important in maintaining the integrity of CSCs in ovarian cancer. [ABSTRACT FROM AUTHOR]

LASP-1 was identified as a protein following mass spectrometric analysis of phosphoproteins consequent to signaling by ErbB2 in SKOV-3 cells. It has been previously identified as an oncogene and is located on chromosomal arm 17q 0.76 Mb centromeric to ErbB2. It is expressed in serous ovarian cancer cell lines as a 40 kDa protein. In SKOV-3 cells, it was phosphorylated and was inhibited by Lapatinib and CP7274714. LASP-1 co-immunoprecipitated with ErbB2 in SKOV-3 cells, suggesting a direct interaction. This interaction and phosphorylation were independent of the kinase activity of ErbB2. Moreover, the binding of LASP-1 to ErbB2 was independent of the tyrosine phosphorylation of LASP-1. LASP-1 was neither expressed on the surface epithelium of the normal ovary nor in the fallopian tube. It was expressed in 28% of ovarian tumours (n = 101) that did not significantly correlate with other clinical factors. In tumours from patients with invasive ductal carcinoma of the breast who had ErbB2 amplification (3+), LASP-1 was expressed in 3/20 (P < 0.001). Analysis of the expression of an independent dataset of ovarian and breast tumours from TCGA showed the significant co-occurrence of ErbB2 and LASP-1 (P < 0.01). These results suggest that LASP-1 and ErbB2 interaction could be important in the pathogenesis of ovarian cancer. [ABSTRACT FROM AUTHOR]