Publications
197 results found
Bidard F-C, Peeters D, Fehm T, et al., 2016, Circulating tumor cells count-based nomograms to predict survival of metastatic breast cancer patients: Results from the European pooled analysis, 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Pardo OE, Munro CE, Castellano L, et al., 2016, miR-515-5p controls cancer cell migration through MARK4 regulation, EMBO Reports, Vol: 17, Pages: 570-584, ISSN: 1469-221X
Here we show that miR-515-5p inhibits cancer cell migration and metastasis. RNA-seqanalyses of both estrogen receptor-positive and negative breast cancer cells overexpressingmiR-515-5p reveals down-regulation of NRAS, FZD4, CDC42BPA, PIK3C2Band MARK4 mRNAs. We demonstrate that miR-515-5p inhibits MARK4 directly 3’UTRinteraction and that MARK4 knockdown mimics the effect of miR-515-5p on breast andlung cancer cell migration. MARK4 over-expression rescues the inhibitory effects of miR-515-5p, suggesting miR-515-5p mediates this process through MARK4 down-regulation.Furthermore, miR-515-5p expression is reduced in metastases compared to primarytumours derived from both in vivo xenografts and samples from patients with breastcancer. Conversely, miR-515-5p overexpression prevents tumour cell dissemination ina mouse metastatic model. Moreover, high miR-515-5p and low MARK4 expressioncorrelate with increased breast and lung cancer patients’ survival, respectively. Takentogether, these data demonstrate the importance of miR-515-5p/MARK4 regulation incell migration and metastasis across two common cancers.
Mato Prado M, Frampton AE, Stebbing J, et al., 2016, Single-cell sequencing in cancer research., Expert Review of Molecular Diagnostics, Vol: 16, Pages: 1-5, ISSN: 1473-7159
Genome-wide single-cell sequencing investigations have the potential to classify individual cells within a tumor mass. In recent years, various single-cell DNA and RNA quantification techniques have facilitated significant advances in our ability to classify subpopulations of cells within a heterogeneous population. These approaches provide the possibility of unraveling the complex variability in genetic, epigenetic and transcriptional interactions that occur within identical cells in a tumor. This should enhance our knowledge of the underlying biological phenotypes and could have a huge impact in designing more precise anticancer treatments in order to improve outcomes and avoid tumor resistance. In addition, single-cell sequencing analysis has the potential to allow the development of better diagnostic and prognostic biomarkers, and thus aid the delivery of more personalized targeted cancer therapy. Nevertheless, further research is still required to overcome technical, biological and computational problems before clinical application.
Krell J, Stebbing J, Carissimi C, et al., 2015, TP53 regulates miRNA association with AGO2 to remodel the miRNA-mRNA interaction network., Genome Research, ISSN: 1549-5469
DNA damage activates TP53-regulated surveillance mechanisms that are crucial in suppressing tumorigenesis. TP53 orchestrates these responses directly by transcriptionally modulating genes, including microRNAs (miRNAs), and by regulating miRNA biogenesis through interacting with the DROSHA complex. However, whether the association between miRNAs and AGO2 is regulated following DNA damage is not yet known. Here we show that, following DNA damage, TP53 interacts with AGO2 to induce or reduce AGO2's association of a subset of miRNAs, including multiple let-7 family members. Furthermore, we show that specific mutations in TP53 decrease rather than increase the association of let-7 family miRNAs, reducing their activity without preventing TP53 from interacting with AGO2. This is consistent with the oncogenic properties of these mutants. Using AGO2 RIP-seq and PAR-CLIP-seq we show that the DNA-damage-induced increase in binding of let-7 family members to the RISC complex is functional. We unambiguously determine the global miRNA-mRNA interaction networks involved in the DNA damage response, validating them through the identification of miRNA-target chimeras formed by endogenous ligation reactions. We find that the target complementary region of the let-7 seed tends to have highly fixed positions and more variable ones. Additionally, we observe that miRNAs whose cellular abundance or differential association with AGO2 is regulated by TP53 are involved in an intricate network of regulatory feedback and feedforward circuits. TP53-mediated regulation of AGO2-miRNA interaction represents a new mechanism of miRNA regulation in carcinogenesis.
Frampton AE, Krell J, Gall TMH, et al., 2015, miR-15b and miR-17 Are Tumor-derived Plasma MicroRNAs Dysregulated in Colorectal Neoplasia, Annals of Surgery, Vol: 262, Pages: e61-e61, ISSN: 0003-4932
Cathcart P, Lucchesi W, Ottaviani S, et al., 2015, Noncoding RNAs and the control of signalling via nuclear receptor regulation in health and disease, BEST PRACTICE & RESEARCH CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 29, Pages: 529-543, ISSN: 1521-690X
Prado MM, Frampton AE, Stebbing J, et al., 2015, Gene of the month: NANOG, Journal of Clinical Pathology, Vol: 68, Pages: 763-765, ISSN: 0021-9746
Frampton AE, Krell J, Jamieson NB, et al., 2015, microRNAs with prognostic significance in pancreatic ductal adenocarcinoma: A meta-analysis, European Journal of Cancer, Vol: 51, Pages: 1389-1404, ISSN: 1879-0852
BackgroundReports have described the prognostic relevance of microRNAs (miRNAs) in patients treated for pancreatic ductal adenocarcinoma (PDAC). However, many of these include small numbers of patients. To increase statistical power and improve translation, we performed a systematic review and meta-analysis to determine a pooled conclusion. We examined the impact of miRNAs on overall survival (OS) and disease-free survival (DFS) in PDAC.MethodsEligible studies were identified and quality assessed using multiple search strategies (last search December 2014). Data were collected from studies correlating clinical outcomes with dysregulated tumoural or blood miRNAs. Studies were pooled, and combined hazard ratios (HRs) with 95% confidence intervals (CIs) were used to estimate strength of the associations.ResultsTwenty studies involving 1525 patients treated for PDAC were included. After correcting for publication bias, OS was significantly shortened in patients with high tumoural miR-21 (adjusted HR = 2.48; 1.96–3.14). This result persisted when only studies adjusting for adjuvant chemotherapy were combined (adjusted HR = 2.72; 1.91–3.89). High miR-21 also predicted reduced DFS (adjusted HR = 3.08; 1.78–5.33). Similarly, we found significant adjusted HRs for poor OS for high miR-155, high miR-203, and low miR-34a; and unadjusted HRs for high miR-222 and high miR-10b. The small number of studies, limited number of miRNAs and paucity of multivariate analyses are the limitations of our study.ConclusionsThis is the first rigorous pooled analysis assessing miRNAs as prognostic biomarkers in PDAC. Tumoural miR-21 overexpression emerged as an important predictor of poor prognosis after PDAC resection independent of other clinicopathologic factors, including adjuvant chemotherapy use.
Roca-Alonso L, Castellano L, Mills A, et al., 2015, Myocardial MiR-30 downregulation triggered by doxorubicin drives alterations in beta-adrenergic signaling and enhances apoptosis, Cell Death & Disease, Vol: 6, ISSN: 2041-4889
The use of anthracyclines such as doxorubicin (DOX) has improved outcome in cancer patients, yet associated risks ofcardiomyopathy have limited their clinical application. DOX-associated cardiotoxicity is frequently irreversible and typicallyprogresses to heart failure (HF) but our understanding of molecular mechanisms underlying this and essential for development ofcardioprotective strategies remains largely obscure. As microRNAs (miRNAs) have been shown to play potent regulatory roles inboth cardiovascular disease and cancer, we investigated miRNA changes in DOX-induced HF and the alteration of cellularprocesses downstream. Myocardial miRNA profiling was performed after DOX-induced injury, either via acute application toisolated cardiomyocytes or via chronic exposure in vivo, and compared with miRNA profiles from remodeled hearts followingmyocardial infarction. The miR-30 family was downregulated in all three models. We describe here that miR-30 act regulating theβ-adrenergic pathway, where preferential β1- and β2-adrenoceptor (β1AR and β2AR) direct inhibition is combined with Giα-2targeting for fine-tuning. Importantly, we show that miR-30 also target the pro-apoptotic gene BNIP3L/NIX. In aggregate, wedemonstrate that high miR-30 levels are protective against DOX toxicity and correlate this in turn with lower reactive oxygenspecies generation. In addition, we identify GATA-6 as a mediator of DOX-associated reductions in miR-30 expression. Inconclusion, we describe that DOX causes acute and sustained miR-30 downregulation in cardiomyocytes via GATA-6. miR-30overexpression protects cardiac cells from DOX-induced apoptosis, and its maintenance represents a potential cardioprotectiveand anti-tumorigenic strategy for anthracyclines.
Frampton AE, Stebbing J, Gall TMH, et al., 2015, Activating mutations of <i>GNAS</i> and <i>KRAS</i> in cystic fluid can help detect intraductal papillary mucinous neoplasms of the pancreas, EXPERT REVIEW OF MOLECULAR DIAGNOSTICS, Vol: 15, Pages: 325-328, ISSN: 1473-7159
- Author Web Link
- Cite
- Citations: 7
Frampton AE, Castellano L, Colombo T, et al., 2015, Integrated molecular analysis to investigate the role of microRNAs in pancreatic tumour growth and progression, LANCET, Vol: 385, Pages: 37-37, ISSN: 0140-6736
- Author Web Link
- Cite
- Citations: 8
Krell J, Stebbing J, Frampton AE, et al., 2015, The role of TP53 in miRNA loading onto AGO2 and in remodelling the miRNA-mRNA interaction network, LANCET, Vol: 385, Pages: 15-15, ISSN: 0140-6736
- Author Web Link
- Cite
- Citations: 3
Savage P, Cooke R, O'Nions J, et al., 2015, Effects of single-agent and combination chemotherapy for gestational trophoblastic tumors on risks of second malignancy and early menopause, Journal of Clinical Oncology, Vol: 33, Pages: 472-U132, ISSN: 0732-183X
PurposeTo assess the risks of second malignancy and early menopause in a large cohort of patients with gestational trophoblastic tumor who were treated with chemotherapy.Patients and MethodsA survey of patients treated at Charing Cross Hospital between 1958 and 2000 was performed in 2006 to assemble incidence data for subsequent malignancies and the age at menopause. Treatment records were reviewed for the regimens and durations, and the incidence of subsequent malignancies was compared with that in the national age-matched population.ResultsData were obtained for 1,903 patients, with a mean follow-up of 16.9 years. Eighty-six patients developed a subsequent malignancy compared with an expected number of 79 (standardized incidence ratio [SIR], 1.1; 95% CI, 0.9 to 1.3). The overall risk was low for patients treated with single-agent methotrexate and folinic acid (MTX-FA; SIR, 0.7; 95% CI, 0.5 to 1.1) and also for patients treated with etoposide, methotrexate, and dactinomycin followed by cyclophosphamide and vincristine on alternating weeks (EMA-CO) with an SIR of 0.9 (95% CI, 0.4 to 2.2), but there were significantly increased risks of oral cancer, melanoma, meningioma, and leukemia. The cumulative risk of early menopause was low after MTX-FA but was substantial after EMA-CO, reaching 13% by age 40 years and 36% by age 45 years.ConclusionSubsequent cancer risks for patients cured of gestational trophoblastic tumors with modern chemotherapy appear similar to those of the normal population with no overall increased risk of malignancy after MTX-FA or EMA-CO. However, there was evidence of an increased risk of leukemia after EMA-CO and some evidence of other site-specific increased risks based on small patient numbers. All major treatments except MTX-FA increased the risk of early menopause.
Alshaker H, Wang Q, Frampton AE, et al., 2015, Sphingosine kinase 1 contributes to leptin-induced STAT3 phosphorylation through IL-6/gp130 transactivation in oestrogen receptor-negative breast cancer, BREAST CANCER RESEARCH AND TREATMENT, Vol: 149, Pages: 59-67, ISSN: 0167-6806
- Author Web Link
- Cite
- Citations: 25
Alshaker H, Krell J, Frampton AE, et al., 2015, Leptin receptor-dependent and -independent STAT3 phosphorylation in oestrogen receptor-negative breast cancer, INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, Vol: 36, Pages: S6-S6, ISSN: 1107-3756
Castellano L, Rizzi E, Krell J, et al., 2015, The germline of the malaria mosquito produces abundant miRNAs, endo-siRNAs, piRNAs and 29-nt small RNAs, Bmc Genomics, Vol: 16
Badreldin W, Krell J, Chowdhury S, et al., 2014, The efficacy of irinotecan, paclitaxel, and oxaliplatin (IPO) in relapsed germ cell tumors with high dose chemotherapy as consolidation- a non-cisplatin- based induction approach., BJU International, Vol: 117, Pages: 418-423, ISSN: 1464-4096
OBJECTIVES: To determine the outcome of an expanded cohort of patients with relapsed germ cell tumors (GCT) treated with a salvage chemotherapy regimen consisting of irinotecan, paclitaxel and oxaliplatin (IPO) and assess the role of IPO as an alternative to standard cisplatin-based chemotherapy regimens in this setting. PATIENTS AND METHODS: The results of 72 consecutive patients were reviewed retrospectively. IPO was used either as a second-line treatment (n=29), of which 20 patients subsequently received high-dose chemotherapy (HDCT), or third-line (n=43), of which 32 patients proceeded to HDCT. RESULTS: The 2-year PFS and 3-year OS rates for the whole cohort were 30.2% (95%CI 17.3-40.5%) and 33.4% (95%CI: 20.1-43.8 %) respectively. CR was achieved in 3%, m-ve PR in 41%, m+ve PR in 18%, SD in 17% and PD in 20%. In the second-line setting, the 2-year PFS rate was 43.5% (95%CI: 21.7-60.8%) and 3-year OS 49.1% (95%CI: 24.2-65.1%). In the third-line setting, the 2-year PFS rate was 21.0% (95%CI 9.5-35.4%) and the 3-year OS rate was 23.9% (95%CI 11.7-38.2).According to the current international prognostic factor study group criteria for first relapse for the high and very high risk group the 2 year PFS rates were 50% and 30% respectively. There were 2 treatment related deaths from IPO, and 4 from HDCT. Grade 3 or 4 toxicities included neutropenia (35%), thrombocytopenia (18%), infection (15%), diarrhea (11%) and lethargy (8%). CONCLUSIONS: IPO offers an effective, well-tolerated, non-nephrotoxic alternative to cisplatin-based salvage regimens for patients with relapsed GCT. It appears particularly useful in high risk patients and for those in whom cisplatin is ineffective or contra-indicated.
Stebbing J, Paz K, Schwartz GK, et al., 2014, Patient-derived xenografts for individualized care in advanced sarcoma (vol 120, pg 2006, 2014), CANCER, Vol: 120, Pages: 3588-3588, ISSN: 0008-543X
- Author Web Link
- Cite
- Citations: 1
Alshaker H, Krell J, Frampton AE, et al., 2014, Leptin induces upregulation of sphingosine kinase 1 in oestrogen receptor-negative breast cancer via Src family kinase-mediated, janus kinase 2-independent pathway, Breast Cancer Research, Vol: 16, ISSN: 1465-542X
Introduction: Obesity is a known risk factor for breast cancer. Sphingosine kinase 1 (SK1) is an oncogenic lipidkinase that is overexpressed in breast tumours and linked with poor prognosis, however, its role in obesity-drivenbreast cancer was never elucidated.Methods: Human primary and secondary breast cancer tissues were analysed for SK1 and leptin receptorexpression using quantitative real-time polymerase chain reaction (qRT-PCR) assay. Leptin-induced signalling wasanalysed in human oestrogen receptor (ER)-positive and negative breast cancer cells using Western blotting,qRT-PCR and radiolabelling assays.Results: Our findings show for the first time that human primary breast tumours and associated lymph nodemetastases exhibit a strong correlation between SK1 and leptin receptor expression (Pearson R = 0.78 and R = 0.77,respectively, P <0.001). Both these genes are elevated in metastases of ER-negative patients and show a significantincrease in patients with higher body mass index (BMI). Leptin induces SK1 expression and activation in ER-negativebreast cancer cell lines MDAMB-231 and BT-549, but not in ER-positive cell lines. Pharmacological inhibition andgene knockdown showed that leptin-induced SK1 activity and expression are mediated by activation of extracellularsignal-regulated kinases 1/2 (ERK1/2) and Src family kinase (SFK) pathways, but not by the major pathwaysdownstream of leptin receptor (LEPR) - janus kinase 2 (JAK2) and signal transducer and activator of transcription 3(STAT3). Src-homology 2 domain-containing phosphatase 2 (SHP2) appeared to be key to SK1 activation, and mayfunction as an adaptor protein between SFKs and LEPR. Importantly, leptin-induced breast cancer cell proliferationwas abrogated by SK1-specific small interfering RNA (siRNA).Conclusions: Overall, our findings demonstrate a novel SFK/ERK1/2-mediated pathway that links leptin signallingand expression of oncogenic enzyme SK1 in breast tumours and suggest the potential significance
Alshaker H, Krell J, Yaguee E, et al., 2014, Leptin induces Src/ERK1/2-mediated, upregulation of sphingosine kinase 1 in ER-negative breast cancer: a potential mechanism for obesity driven cancer progression, FEBS EMBO 2014 Conference, Publisher: WILEY-BLACKWELL, Pages: 483-483, ISSN: 1742-464X
Krell J, Stebbing J, 2014, Stage-Stratified Approach to AIDS-Related Kaposi's Sarcoma: Implications for Resource-Limited Environments Reply, JOURNAL OF CLINICAL ONCOLOGY, Vol: 32, Pages: 2514-U162, ISSN: 0732-183X
de Giorgio A, Castellano L, Krell J, et al., 2014, Crosstalk-induced loss of miR-126 promotes angiogenesis, ONCOGENE, Vol: 33, Pages: 3634-3635, ISSN: 0950-9232
- Author Web Link
- Cite
- Citations: 11
Stebbing J, Paz K, Schwartz GK, et al., 2014, Patient-Derived Xenografts for Individualized Care in Advanced Sarcoma, CANCER, Vol: 120, Pages: 2006-2015, ISSN: 0008-543X
- Author Web Link
- Open Access Link
- Cite
- Citations: 125
Krell J, Frampton AE, Mirnezami R, et al., 2014, Growth Arrest-Specific Transcript 5 Associated snoRNA Levels Are Related to p53 Expression and DNA Damage in Colorectal Cancer, PLOS One, Vol: 9, ISSN: 1932-6203
Background: The growth arrest-specific transcript 5 gene (GAS5) encodes a long noncoding RNA (lncRNA) and hosts anumber of small nucleolar RNAs (snoRNAs) that have recently been implicated in multiple cellular processes and cancer.Here, we investigate the relationship between DNA damage, p53, and the GAS5 snoRNAs to gain further insight into thepotential role of this locus in cell survival and oncogenesis both in vivo and in vitro.Methods: We used quantitative techniques to analyse the effect of DNA damage on GAS5 snoRNA expression and to assessthe relationship between p53 and the GAS5 snoRNAs in cancer cell lines and in normal, pre-malignant, and malignanthuman colorectal tissue and used biological techniques to suggest potential roles for these snoRNAs in the DNA damageresponse.Results: GAS5-derived snoRNA expression was induced by DNA damage in a p53-dependent manner in colorectal cancercell lines and their levels were not affected by DICER. Furthermore, p53 levels strongly correlated with GAS5-derived snoRNAexpression in colorectal tissue.Conclusions: In aggregate, these data suggest that the GAS5-derived snoRNAs are under control of p53 and that they havean important role in mediating the p53 response to DNA damage, which may not relate to their function in the ribosome.We suggest that these snoRNAs are not processed by DICER to form smaller snoRNA-derived RNAs with microRNA (miRNA)-like functions, but their precise role requires further evaluation. Furthermore, since GAS5 host snoRNAs are often used asendogenous controls in qPCR quantifications we show that their use as housekeeping genes in DNA damage experimentscan lead to inaccurate results.
Hardt A, Krell J, Wilson PD, et al., 2014, Brain Metastases Associated With Germ Cell Tumors May Be Treated With Chemotherapy Alone, CANCER, Vol: 120, Pages: 1639-1646, ISSN: 0008-543X
- Author Web Link
- Cite
- Citations: 15
Gall TMH, Jacob J, Frampton AE, et al., 2014, Reduced dissemination of circulating tumor cells with no-touch isolation surgical technique in patients with pancreatic cancer, JAMA Surgery, Vol: 149, Pages: 482-485, ISSN: 2168-6254
Roca-Alonso L, Castellano L, Mills A, et al., 2014, Myocardial miR-30 down-regulation triggered by doxorubicin drives alterations in the beta-adrenergic pathway and enhances apoptosis, EUROPEAN JOURNAL OF HEART FAILURE, Vol: 16, Pages: 115-115, ISSN: 1388-9842
Bidard F-C, Peeters DJ, Fehm T, et al., 2014, Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data, The Lancet Oncology, Vol: 15, Pages: 406-414, ISSN: 1213-9432
BackgroundWe aimed to assess the clinical validity of circulating tumour cell (CTC) quantification for prognostication of patients with metastatic breast cancer by undertaking a pooled analysis of individual patient data.MethodsWe contacted 51 European centres and asked them to provide reported and unreported anonymised data for individual patients with metastatic breast cancer who participated in studies between January, 2003, and July, 2012. Eligible studies had participants starting a new line of therapy, data for progression-free survival or overall survival, or both, and CTC quantification by the CellSearch method at baseline (before start of new treatment). We used Cox regression models, stratified by study, to establish the association between CTC count and progression-free survival and overall survival. We used the landmark method to assess the prognostic value of CTC and serum marker changes during treatment. We assessed the added value of CTCs or serum markers to prognostic clinicopathological models in a resampling procedure using likelihood ratio (LR) χ 2 statistics.Findings17 centres provided data for 1944 eligible patients from 20 studies. 911 patients (46·9%) had a CTC count of 5 per 7·5 mL or higher at baseline, which was associated with decreased progression-free survival (hazard ratio [HR] 1·92, 95% CI 1·73–2·14, p<0·0001) and overall survival (HR 2·78, 95% CI 2·42–3·19, p<0·0001) compared with patients with a CTC count of less than 5 per 7·5 mL at baseline. Increased CTC counts 3–5 weeks after start of treatment, adjusted for CTC count at baseline, were associated with shortened progression-free survival (HR 1·85, 95% CI 1·48–2·32, p<0·0001) and overall survival (HR 2·26, 95% CI 1·68–3·03) as were increased CTC counts after 6–8 weeks (progression-free survival HR 2·20
Frampton AE, Giovannetti E, Jamieson NB, et al., 2014, A microRNA meta-signature for pancreatic ductal adenocarcinoma, EXPERT REVIEW OF MOLECULAR DIAGNOSTICS, Vol: 14, Pages: 267-271, ISSN: 1473-7159
- Author Web Link
- Cite
- Citations: 25
Krell J, Stebbing J, 2014, Broader Implications of a Stage-Guided Stratified Therapeutic Approach for AIDS-Related Kaposi's Sarcoma, JOURNAL OF CLINICAL ONCOLOGY, Vol: 32, Pages: 373-375, ISSN: 0732-183X
- Author Web Link
- Cite
- Citations: 10
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.