scholarly journals FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy

2019 ◽  
Author(s):  
Carlos J. Díaz Osterman ◽  
Duygu Ozmadenci ◽  
Elizabeth G. Kleinschmidt ◽  
Kristin N. Taylor ◽  
Allison M. Barrie ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Gene Copy ◽  
Platinum Resistance ◽  
List Type ◽  
High Grade ◽  
Cancer Resistance ◽  
Platinum Chemotherapy

AbstractGene copy number changes, cancer stem cell (CSC) increases, and platinum chemotherapy resistance contribute to poor prognosis in patients with recurrent high grade serous ovarian cancer (HGSOC). CSC phenotypes involving Wnt-β-catenin and aldehyde dehydrogenase activities, platinum resistance, and tumor initiating frequency are here associated with spontaneous genetic gains, including genes encodingKRAS,MYCandFAK, in a new murine model of ovarian cancer (KMF). Noncanonical FAK signaling was sufficient to sustain human and KMF tumorsphere proliferation, CSC survival, and platinum resistance. Increased FAK tyrosine phosphorylation occurred in HGSOC patient tumors surviving neo-adjuvant platinum and paclitaxel chemotherapy and platinum resistant tumorspheres acquired FAK dependence for growth. Importantly, combining a pharmacologic FAK inhibitor with platinum overcame chemoresistance and triggered apoptosisin vitroandin vivo. Knockout, rescue, genomic and transcriptomic analyses collectively identified more than 400 genes regulated along a FAK/β-catenin/Myc axis impacting stemness and DNA repair in HGSOC, with 66 genes gained in a majority of Cancer Genome Atlas samples. Together, these results support combinatorial testing of FAK inhibitors for the treatment of recurrent ovarian cancer.Graphical SummaryKey PointsHigh grade serous ovarian carcinoma tumors containPTK2(FAK) 8q24.3 gains associated with prognostic differences.KMF, a new murine ovarian cancer model withK-Ras,Myc, andFAK gene gains and intrinsic platinum resistance.FAK activation in tumors surviving platinum chemotherapy promotes cancer stem cell survival.FAK facilitates a β-catenin-Myc signaling axis controlling gene expression supporting platinum resistance.FAK activity is essential for KMF tumor growth and is a targetable cellular adaptation of platinum resistance.

scholarly journals FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Carlos J Diaz Osterman ◽  
Duygu Ozmadenci ◽  
Elizabeth G Kleinschmidt ◽  
Kristin N Taylor ◽  
Allison M Barrie ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Chemotherapy Resistance ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Platinum Resistance ◽  
Cancer Resistance ◽  
Copy Number Alterations ◽  
Neo Adjuvant Chemotherapy ◽  
Platinum Chemotherapy ◽  
Repair Genes

Gene copy number alterations, tumor cell stemness, and the development of platinum chemotherapy resistance contribute to high-grade serous ovarian cancer (HGSOC) recurrence. Stem phenotypes involving Wnt-β-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere formation are here associated with spontaneous gains in Kras, Myc and FAK (KMF) genes in a new aggressive murine model of ovarian cancer. Adhesion-independent FAK signaling sustained KMF and human tumorsphere proliferation as well as resistance to cisplatin cytotoxicity. Platinum-resistant tumorspheres can acquire a dependence on FAK for growth. Accordingly, increased FAK tyrosine phosphorylation was observed within HGSOC patient tumors surviving neo-adjuvant chemotherapy. Combining a FAK inhibitor with platinum overcame chemoresistance and triggered cell apoptosis. FAK transcriptomic analyses across knockout and reconstituted cells identified 135 targets, elevated in HGSOC, that were regulated by FAK activity and β-catenin including Myc, pluripotency and DNA repair genes. These studies reveal an oncogenic FAK signaling role supporting chemoresistance.

New Markers For Human Ovarian Cancer That Link Platinum Resistance To The Cancer Stem Cell Phenotype And Define New Therapeutic Combinations And Diagnostic Tools

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S119-S119
Author(s):  
Y S Kamel
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Bioinformatics Analysis ◽  
Genetic Alterations ◽  
Ovarian Tumors ◽  
Cell Phenotype ◽  
Platinum Resistance

Abstract Introduction/Objective Ovarian cancer is the leading cause of gynecologic cancer-related death, due in part to a late diagnosis and a high rate of recurrence. Primary and acquired platinum resistance is related to a low response probability to subsequent lines of treatment and to a poor survival. Therefore, a comprehensive understanding of the mechanisms that drive platinum resistance is urgently needed. Methods We used bioinformatics analysis of public databases and RT-qPCR to quantitate the relative gene expression profiles of ovarian tumors. Many of the dysregulated genes were cancer stem cell (CSC) factors, and we analyzed its relation to therapeutic resistance in human primary tumors. We also performed clustering and in vitro analyses of therapy cytotoxicity in tumorspheres. Results Using bioinformatics analysis, we identified transcriptional targets that are common endpoints of genetic alterations linked to platinum resistance in ovarian tumors. Most of these genes are grouped into 4 main clusters related to the CSC phenotype, including the DNA damage, Notch and C-KIT/MAPK/MEK pathways. The relative expression of these genes, either alone or in combination, is related to prognosis and provide a connection between platinum resistance and the CSC phenotype. However, the expression of the CSC-related markers was heterogeneous in the resistant tumors, most likely because there were different CSC pools. Furthermore, our in vitro results showed that the inhibition of the CSC-related targets lying at the intersection of the DNA damage, Notch and C-KIT/MAPK/MEK pathways sensitize CSC-enriched tumorspheres to platinum therapies, suggesting a new option for the treatment of patients with platinum-resistant ovarian cancer. Conclusion The current study presents a new approach to target the physiology of resistant ovarian tumor cells through the identification of core biomarkers. We hypothesize that the identified mutations confer platinum resistance by converging to activate a few pathways and to induce the expression of a few common, measurable and targetable essential genes. These pathways include the DNA damage, Notch and C-KIT/MAPK/MEK pathways. Finally, the combined inhibition of one of these pathways with platinum treatment increases the sensitivity of CSC-enriched tumorspheres to low doses of platinum, suggesting a new treatment for ovarian cancer.

scholarly journals ZIP4 Is a Novel Cancer Stem Cell Marker in High-Grade Serous Ovarian Cancer

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3692
Author(s):  
Qipeng Fan ◽  
Wen Zhang ◽  
Robert E. Emerson ◽  
Yan Xu
Keyword(s):  
Ovarian Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Stem Cell Marker ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Upstream Regulator ◽  
Genetic Compensation

High-grade serous ovarian cancer (HGSOC) is one of the most deadly and heterogenic cancers. We have recently shown that ZIP4 (gene name SLC39A4), a zinc transporter, is functionally involved in cancer stem cell (CSC)-related cellular activities in HGSOC. Here, we identified ZIP4 as a novel CSC marker in HGSOC. Fluorescence-activated cell sorter (FACS)-sorted ZIP4+, but not ZIP4− cells, formed spheroids and displayed self-renewing and differentiation abilities. Over-expression of ZIP4 conferred drug resistance properties in vitro. ZIP4+, but not ZIP4− cells, formed tumors/ascites in vivo. We conducted limiting dilution experiments and showed that 100–200 ZIP4+ cells from both PE04 and PEA2 cells formed larger tumors than those from 100–200 ALDH+ cells in mice. Mechanistically, we found that ZIP4 was an upstream regulator of another CSC-marker, NOTCH3, in HGSOC cells. NOTCH3 was functionally involved in spheroid formation in vitro and tumorigenesis in vivo in HGSOC. Genetic compensation studies showed that NOTCH3, but not NOTCH1, was a critical downstream mediator of ZIP4. Furthermore, NOTCH3, but not NOTCH1, physically bound to ZIP4. Collectively, our data suggest that ZIP4 is a novel CSC marker and the new ZIP4-NOTCH3 axis represents important therapeutic targets in HGSOC.

scholarly journals MET Expression and Cancer Stem Cell Networks Impact Outcome in High-Grade Serous Ovarian Cancer

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 742
Author(s):  
Maria Bååth ◽  
Jenny-Maria Jönsson ◽  
Sofia Westbom Fremer ◽  
Laura Martín de la Fuente ◽  
Lena Tran ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cell ◽  
Cell Lines ◽  
Synergistic Effects ◽  
Combined Treatment ◽  
Rank Test ◽  
High Grade ◽  
Cancer Types ◽  
Cell Networks

Overexpression of the receptor tyrosine kinase MET has been linked to poor survival in several cancer types, and MET has been suggested to interact with stem cell networks. In vitro studies have further suggested a possible benefit of a combined treatment using PARP and MET inhibitors. We used a tissue microarray (TMA) with 130 samples of advanced-stage high-grade serous fallopian tube/ovarian cancer (HGSC) to investigate the prognostic value of MET protein expression alone and in combination with the stem cell factor SOX2. The possible synergistic effects of a PARP and MET inhibitor treatment were evaluated in two cell lines with BRCA1 or BRCA2 deficiency and in their BRCA1/2-proficient counterparts. Patients with tumors positive for MET had worse overall survival (log-rank test, p = 0.015) compared to patients with MET-negative tumors. The prognostic role of MET was even more prominent in the subgroup of patients with SOX2-negative tumors (p = 0.0081). No synergistic effects of the combined treatment with PARP and MET inhibitors were found in the cell lines examined. We conclude that MET expression could be used as a marker for OS in HGSC and that stemness should be taken into consideration when evaluating the mechanisms of this effect.

scholarly journals Histone Demethylase KDM4C Is Required for Ovarian Cancer Stem Cell Maintenance

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Guo-Qing Chen ◽  
Ping Ye ◽  
Rong-Song Ling ◽  
Fa Zeng ◽  
Xiong-Shan Zhu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Histone Demethylase ◽  
Potential Therapeutic Target ◽  
Stem Cell Maintenance ◽  
Platinum Based Chemotherapy ◽  
Current Therapies ◽  
Sphere Formation

Ovarian cancer is a highly deadly disease, which is often diagnosed at a late stage with metastases. However, most ovarian cancers relapse after surgery combined with platinum-based chemotherapy. Cancer stem cells (CSCs) are stem-like cells that possess high tumorigenic capability and display higher resistant capability against current therapies. However, our knowledge of ovarian CSCs and their molecular mechanism remains sparse. In the current study, we found that KDM4C, a histone demethylase, was required for ovarian cancer stem cell (CSC) maintenance. Depletion of KDM4C significantly reduced the CSC population and sphere formation in vitro. Moreover, we found that KDM4C can regulate the expression of stem cell factor OCT-4 via binding to its promoter. These data indicate that KDM4C is relevant for ovarian CSC maintenance and underscore its importance as a potential therapeutic target.

Abstract 1562: Germline polymorphisms in cancer stem cell genes associate with survival among women with high-grade serous ovarian cancer

2019 ◽  
Author(s):  
Brett M. Reid ◽  
Jennifer B. Permuth ◽  
Zhihua Chen ◽  
Ann Chen ◽  
Thomas A. Sellers ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
High Grade ◽  
Serous Ovarian Cancer

Abstract 1562: Germline polymorphisms in cancer stem cell genes associate with survival among women with high-grade serous ovarian cancer

2019 ◽  
Author(s):  
Brett M. Reid ◽  
Jennifer B. Permuth ◽  
Zhihua Chen ◽  
Ann Chen ◽  
Thomas A. Sellers ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
High Grade ◽  
Serous Ovarian Cancer
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