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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]

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]