Identifying novel hypoxia-associated markers of chemoresistance in ovarian cancer

McEvoy, Lynda; O’Toole, Sharon; Spillane, Cathy; Martín, C; Gallagher, Michael; Stordal, Britta K.; Blackshields, Gordon; Sheils, Orla; O’Leary, John

doi:10.1186/s12885-015-1539-8

Cited by 41 publications

(30 citation statements)

References 74 publications

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“…Irradiation (two meta-analyses for cancer and embryonic cells) E-GEOD-59732 [ 111 ] Breast cancer 24 48 48 E-GEOD-59861 [ 112 ] Skin fibroblasts 0, 3, 6, 12, 24 4 12 IV. Hypoxia E-GEOD-18494 [ 113 ] Hepatocyte carcinoma, glioblastoma, breast cancer 12 9 9 E-GEOD-53012 [ 114 ] Prostate cancer, ovarian cancer, melanoma 72 9 9 E-MTAB-3645 [ 109 ] Ovarian cancer 72 3 3 E-GEOD-17188 [ 115 ] Breast cancer 24 4 4 V. Tyrosine kinase inhibitors E-TABM-585 [ 116 ] Lung cancer 20 21 27 VI. Topoisomerase inhibitors E-GEOD-47013 [ 117 ] Multiple myeloma – 3 3 E-GEOD-13477 [ 118 ] Breast cancer 24 2 2 E-GEOD-19638 [ 119 ] Breast cancer – 2 2 E-GEOD-39870 [ 120 ] Breast cancer – 3 3 Splicing analysis GSE69405 [ 37 ] Lung adenocarcinoma 48 12 12 GSE89127 [ 34 ] ...…”

Section: Methodsmentioning

confidence: 99%

Therapy-induced stress response is associated with downregulation of pre-mRNA splicing in cancer cells

et al. 2018

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BackgroundAbnormal pre-mRNA splicing regulation is common in cancer, but the effects of chemotherapy on this process remain unclear.MethodsTo evaluate the effect of chemotherapy on slicing regulation, we performed meta-analyses of previously published transcriptomic, proteomic, phosphoproteomic, and secretome datasets. Our findings were verified by LC-MS/MS, western blotting, immunofluorescence, and FACS analyses of multiple cancer cell lines treated with cisplatin and pladienolide B.ResultsOur results revealed that different types of chemotherapy lead to similar changes in alternative splicing by inducing intron retention in multiple genes. To determine the mechanism underlying this effect, we analyzed gene expression in 101 cell lines affected by ɣ-irradiation, hypoxia, and 10 various chemotherapeutic drugs. Strikingly, оnly genes involved in the cell cycle and pre-mRNA splicing regulation were changed in a similar manner in all 335 tested samples regardless of stress stimuli. We revealed significant downregulation of gene expression levels in these two pathways, which could be explained by the observed decrease in splicing efficiency and global intron retention. We showed that the levels of active spliceosomal proteins might be further post-translationally decreased by phosphorylation and export into the extracellular space. To further explore these bioinformatics findings, we performed proteomic analysis of cisplatin-treated ovarian cancer cells. Finally, we demonstrated that the splicing inhibitor pladienolide B impairs the cellular response to DNA damage and significantly increases the sensitivity of cancer cells to chemotherapy.ConclusionsDecreased splicing efficiency and global intron retention is a novel stress response mechanism that may promote survival of malignant cells following therapy. We found that this mechanism can be inhibited by pladienolide B, which significantly increases the sensitivity of cancer cells to cisplatin which makes it a good candidate drug for improving the efficiency of cancer therapy.Electronic supplementary materialThe online version of this article (10.1186/s13073-018-0557-y) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Therapy-induced stress response is associated with downregulation of pre-mRNA splicing in cancer cells

et al. 2018

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“…Subsequently, A2780cis cells were found to have retained cisplatin tolerance (IC 50 =11±0.4 μ M, Figure 5a ), in line with our previous description. 13 This indicates that prolonged exposure to cisplatin results in a hard-wired tolerance that is no longer cisplatin dependent. Interestingly, A2780cis parent cells were found to remain highly sensitive to paclitaxel ( Figure 5c ).…”

Section: Resultsmentioning

confidence: 99%

“…Cell lines (A2780/A2780cis) and culturing are as previously described. 13 Where stated, A2780cis cells were cultured in the absence of cisplatin. Cisplatin (Hospira, Maidenhead, UK) was donated by the Aseptic Compounding Unit, St. James’s Hospital, Dublin, Ireland.…”

Section: Methodsmentioning

confidence: 99%

CD10−/ALDH− cells are the sole cisplatin-resistant component of a novel ovarian cancer stem cell hierarchy

et al. 2017

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It is long established that tumour-initiating cancer stem cells (CSCs) possess chemoresistant properties. However, little is known of the mechanisms involved, particularly with respect to the organisation of CSCs as stem-progenitor-differentiated cell hierarchies. Here we aimed to elucidate the relationship between CSC hierarchies and chemoresistance in an ovarian cancer model. Using a single cell-based approach to CSC discovery and validation, we report a novel, four-component CSC hierarchy based around the markers cluster of differentiation 10 (CD10) and aldehyde dehydrogenase (ALDH). In a change to our understanding of CSC biology, resistance to chemotherapy drug cisplatin was found to be the sole property of CD10−/ALDH− CSCs, while all four CSC types were sensitive to chemotherapy drug paclitaxel. Cisplatin treatment quickly altered the hierarchy, resulting in a three-component hierarchy dominated by the cisplatin-resistant CD10−/ALDH− CSC. This organisation was found to be hard-wired in a long-term cisplatin-adapted model, where again CD10−/ALDH− CSCs were the sole cisplatin-resistant component, and all CSC types remained paclitaxel-sensitive. Molecular analysis indicated that cisplatin resistance is associated with inherent- and adaptive-specific drug efflux and DNA-damage repair mechanisms. Clinically, low CD10 expression was consistent with a specific set of ovarian cancer patient samples. Collectively, these data advance our understanding of the relationship between CSC hierarchies and chemoresistance, which was shown to be CSC- and drug-type specific, and facilitated by specific and synergistic inherent and adaptive mechanisms. Furthermore, our data indicate that primary stage targeting of CD10−/ALDH− CSCs in specific ovarian cancer patients in future may facilitate targeting of recurrent disease, before it ever develops.

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“…[ 64 ] HER3 is downregulated in patients with poor or no response to chemotherapy. [ 65 ] Conversely, HER3 overexpression has been associated with acquired resistance to trastuzumab in ovarian epithelial adenocarcinomas. [ 66 ] In a phase II trial of patients with platinum-resistant ovarian epithelial carcinoma, low HER3 mRNA expression predicted response to gemcitabine plus an anti-HER2 antibody (pertuzumab).…”

Section: The Heregulins-dependent Pathway In Different Cancer Typesmentioning

confidence: 99%

A comprehensive review of heregulins, HER3, and HER4 as potential therapeutic targets in cancer

et al. 2017

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Heregulins (HRGs) bind to the receptors HER3 or HER4, induce receptor dimerization, and trigger downstream signaling that leads to tumor progression and resistance to targeted therapies. Increased expression of HRGs has been associated with worse clinical prognosis; therefore, attempts to block HRG-dependent tumor growth have been pursued. This manuscript summarizes the function and signaling of HRGs and review the preclinical evidence of its involvement in carcinogenesis, prognosis, and treatment resistance in several malignancies such as colorectal cancer, non-small cell lung cancer, ovarian cancer, and breast cancer. Agents in preclinical development and clinical trials of novel therapeutics targeting HRG-dependent signaling are also discussed, including anti-HER3 and -HER4 antibodies, anti-metalloproteinase agents, and HRG fusion proteins. Although several trials have indicated an acceptable safety profile, translating preclinical findings into clinical practice remains a challenge in this field, possibly due to the complexity of downstream signaling and patterns of HRG, HER3 and HER4 expression in different cancer subtypes. Improving patient selection through biomarkers and understanding the resistance mechanisms may translate into significant clinical benefits in the near future.

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Identifying novel hypoxia-associated markers of chemoresistance in ovarian cancer

Cited by 41 publications

References 74 publications

Therapy-induced stress response is associated with downregulation of pre-mRNA splicing in cancer cells

Therapy-induced stress response is associated with downregulation of pre-mRNA splicing in cancer cells

CD10−/ALDH− cells are the sole cisplatin-resistant component of a novel ovarian cancer stem cell hierarchy

A comprehensive review of heregulins, HER3, and HER4 as potential therapeutic targets in cancer

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