British Columbia Cancer Research Center

Vancouver, Canada

British Columbia Cancer Research Center

Vancouver, Canada
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Dawson S.-J.,University of Cambridge | Rueda O.M.,University of Cambridge | Aparicio S.,University of British Columbia | Aparicio S.,British Columbia Cancer Research Center | And 2 more authors.
EMBO Journal | Year: 2013

Breast cancer is a group of heterogeneous diseases that show substantial variation in their molecular and clinical characteristics. This heterogeneity poses significant challenges not only in breast cancer management, but also in studying the biology of the disease. Recently, rapid progress has been made in understanding the genomic diversity of breast cancer. These advances led to the characterisation of a new genome-driven integrated classification of breast cancer, which substantially refines the existing classification systems currently used. The novel classification integrates molecular information on the genomic and transcriptomic landscapes of breast cancer to define 10 integrative clusters, each associated with distinct clinical outcomes and providing new insights into the underlying biology and potential molecular drivers. These findings have profound implications both for the individualisation of treatment approaches, bringing us a step closer to the realisation of personalised cancer management in breast cancer, but also provide a new framework for studying the underlying biology of each novel subtype. © 2013 European Molecular Biology Organization.


Serrano I.,British Columbia Cancer Research Center | McDonald P.C.,British Columbia Cancer Research Center | Lock F.,British Columbia Cancer Research Center | Muller W.J.,McGill University | Dedhar S.,British Columbia Cancer Research Center
Nature Communications | Year: 2013

One of the hallmarks of cancers is the silencing of tumour suppressor genes and pathways. The Hippo tumour suppressor pathway is inactivated in many types of cancers, leading to tumour progression and metastasis. However, the mechanisms of pathway inactivation in tumours remain unclear. Here we demonstrate that integrin-linked kinase (ILK) plays a critical role in the suppression of the Hippo pathway via phospho-inhibition of MYPT1-PP1, leading to inactivation of Merlin. Inhibition of ILK in breast, prostate and colon tumour cells results in the activation of the Hippo pathway components MST1 and LATS1 with concomitant inactivation of YAP/TAZ (Yes-associated protein/transcriptional co-activator with PDZ-binding motif) transcriptional co-activators and TEAD-mediated transcription. Genetic deletion of ILK suppresses ErbB2-driven YAP/TAZ activation in mammary tumours, and its pharmacological inhibition suppresses YAP activation and tumour growth in vivo. Our data demonstrate a role for ILK as a multiple receptor proximal regulator of Hippo tumour suppressor pathway and as a cancer therapeutic target. © 2013 Macmillan Publishers Limited.


Evdokimova V.,Institute of Protein Research | Tognon C.E.,British Columbia Cancer Research Center | Sorensen P.H.B.,British Columbia Cancer Research Center | Sorensen P.H.B.,University of British Columbia
Seminars in Cancer Biology | Year: 2012

Translational regulation is increasingly recognized as a critical mediator of gene expression. It endows cells with the ability to decide when a particular protein is expressed, thereby ensuring proper and prompt cellular responses to environmental cues. This ability to reprogram protein synthesis and to permit the translation of the respective regulatory messages is particularly important in complex changing environments, including embryonic development, wound healing and environmental stress. Not surprisingly, mistakes in this process can lead to cancer. This review will focus on the mechanisms of translational control operating in normal and cancer cells. We discuss the possibility that progression of primary epithelial tumors into a motile mesenchymal-like phenotype during the invasive phase of metastasis is driven, in part, by a switch from cap-dependent to cap-independent translation. © 2012 Elsevier Ltd.


Ma Q.C.,University of British Columbia | Ma Q.C.,British Columbia Cancer Research Center | Ennis C.A.,British Columbia Cancer Research Center | Aparicio S.,University of British Columbia | Aparicio S.,British Columbia Cancer Research Center
Current Opinion in Genetics and Development | Year: 2012

Recent advances in next generation sequencing have greatly enhanced the scope and speed of genomic cancer research. Apart from merely listing identified mutations from cancer genomes sequencing, this review will summarize some insights specifically focusing on the biology of allele generating cancer driver mutations and clonal patterns during tumor evolution. Studies using massively parallel sequencing of primary tumor samples and cancer cell lines have identified neomorphic alleles and other recurrent mutations in proteins involved in chromatin modification and in the regulation of transcription and translation. Further studies with deep sequencing of matched primary and metastatic tumors have also started to characterize distinct patterns of tumor clonal evolution. The development of single cell sequencing is expected to help further elucidate tumor clonality and aid the translation of these discoveries into diagnostic and therapeutic applications. © 2012 Elsevier Ltd.


Roth A.,University of British Columbia | Roth A.,British Columbia Cancer Research Center | Khattra J.,British Columbia Cancer Research Center | Yap D.,British Columbia Cancer Research Center | And 10 more authors.
Nature Methods | Year: 2014

We introduce PyClone, a statistical model for inference of clonal population structures in cancers. PyClone is a Bayesian clustering method for grouping sets of deeply sequenced somatic mutations into putative clonal clusters while estimating their cellular prevalences and accounting for allelic imbalances introduced by segmental copy-number changes and normal-cell contamination. Single-cell sequencing validation demonstrates PyClone's accuracy. © 2014 Nature America, Inc. All rights reserved.


Tognon C.E.,British Columbia Cancer Research Center | Sorensen P.H.B.,British Columbia Cancer Research Center
Expert Opinion on Therapeutic Targets | Year: 2012

Introduction: The IGF system controls growth, differentiation, and development at the cellular, organ and organismal levels. IGF1 receptor (IGF1R) signaling is dysregulated in many cancers. Numerous clinical trials are currently assessing therapies that inhibit either growth factor binding or IGF1R itself. Therapeutic benefit, often in the form of stable disease, has been reported for many different cancer types. Areas covered: Canonical IGF signaling and non-canonical pathways involved in carcinogenesis. Three recent insights into IGF1R signaling, namely hybrid receptor formation with insulin receptor (INSR), insulin receptor substrate 1 nuclear translocation, and evidence for IGF1R/INSR as dependence receptors. Different approaches to targeting IGF1R and mechanisms of acquired resistance. Possible mechanisms by which IGF1R signaling supports carcinogenesis and specific examples in different human tumors. Expert opinion: Pre-clinical data justifies IGF1R as a target and early clinical trials have shown modest efficacy in selected tumor types. Future work will focus upon assessing the usefulness or disadvantages of simultaneously targeting the IGF1R and INSR, biomarker development to identify potentially responsive patients, and the use of IGF1R inhibitors in combination therapies or as an adjunct to conventional chemotherapy. © 2012 Informa UK, Ltd.


Kannan N.,British Columbia Cancer Research Center | Nguyen L.V.,British Columbia Cancer Research Center | Eaves C.J.,British Columbia Cancer Research Center
Nature Cell Biology | Year: 2014

Heterogeneity in tumour cell properties underlies many treatment failures. Understanding the sources of such heterogeneity has proved to be challenging, but remains critical to improving patient outcomes. Integrin α v β 3 expression in multiple types of solid tumour stem cells is now shown to control a pro-survival pathway that contributes to therapy resistance. © 2014 Macmillan Publishers Limited. All rights reserved.


Olive P.L.,British Columbia Cancer Research Center
Radiotherapy and Oncology | Year: 2011

The application of biological responses of tumours to predict clinical responses to treatment represents a challenging goal with the potential to inform treatment decisions and improve outcome. If tumour cell death is the result of the inability of a cell to repair complex DNA damage, and if γH2AX foci mark sites of unrepaired double-strand breaks, then it may be possible to use residual γH2AX foci to identify treatment-resistant tumour cells early in the course of therapy. This review will highlight some of the evidence that supports the idea that residual γH2AX foci, within certain limitations, may be useful as an early indicator of tumour response to radiotherapy in situ, either alone or in combination with chemotherapy. © 2011 Elsevier Ireland Ltd. All rights reserved.


Coe B.P.,British Columbia Cancer Research Center | Chari R.,British Columbia Cancer Research Center | MacAulay C.,British Columbia Cancer Research Center | Lam W.L.,British Columbia Cancer Research Center
Nucleic Acids Research | Year: 2010

The availability of high resolution array comparative genomic hybridization (CGH) platforms has led to increasing complexities in data analysis. Specifically, defining contiguous regions of alterations or segmentation can be computationally intensive and popular algorithms can take hours to days for the processing of arrays comprised of hundreds of thousands to millions of elements. Additionally, tumors tend to demonstrate subtle copy number alterations due to heterogeneity, ploidy and hybridization effects. Thus, there is a need for fast, sensitive array CGH segmentation and alteration calling algorithms. Here, we describe Fast Algorithm for Calling After Detection of Edges (FACADE), a highly sensitive and easy to use algorithm designed to rapidly segment and call high resolution array data. © The Author(s) 2010. Published by Oxford University Press.


Olive P.L.,British Columbia Cancer Research Center | Banath J.P.,British Columbia Cancer Research Center | Durand R.E.,British Columbia Cancer Research Center
Radiation Research | Year: 2012

A method for measuring DNA damage to individual cells, based on the technique of microelectrophoresis, was described by Ostling and Johanson in 1984 (Biochem. Biophys. Res. Commun. 123, 291298). Cells embedded in agarose are lysed, subjected briefly to an electric field, stained with a fluorescent DNA-binding stain, and viewed using a fluorescence microscope. Broken DNA migrates farther in the electric field, and the cell then resembles a comet with a brightly fluorescent head and a tail region which increases as damage increases. We have used video image analysis to define appropriate features of the comet as a measure of DNA damage, and have quantified damage and repair by ionizing radiation. The assay was optimized for lysing solution, lysing time, electrophoresis time, and propidium iodide concentration using Chinese hamster V79 cells. To assess heterogeneity of response of normal versus malignant cells, damage to both tumor cells and normal cells within mouse SCC-VII tumors was assessed. Tumor cells were separated from macrophages using a cell-sorting method based on differential binding of FITC-conjugated goat anti-mouse IgG. The tail moment, the product of the amount of DNA in the tail and the mean distance of migration in the tail, was the most informative feature of the comet image. Tumor and normal cells showed significant heterogeneity in damage produced by ionizing radiation, although the average amount of damage increased linearly with dose (015 Gy) and suggested similar net radiosensitivities for the two cell types. Similarly, DNA repair rate was not significantly different for tumor and normal cells, and most of the cells had repaired the damage by 30 min following exposure to 15 Gy. The heterogeneity in response did not appear to be a result of differences in response through the cell cycle. © 2012 by Radiation Research Society. All rights of reproduction in any form reserved.

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