• Sorensen, Poul

    Titles

    Investigator, Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital
    Professor, Department of Pathology, University of British Columbia

    Degrees / Designations
    MD, PhD
    Primary Area of Research
    Childhood Diseases
    Secondary Area(s) of Research
    Phone
    604-675-8202
    Fax
    604-675-8218
    Lab Phone
    604-675-8000 ext. 7551
    Assistant
    Shelley Berkow
    Assistant Phone
    604-675-8203
    Mailing Address

    BC Cancer Agency Research Centre
    675 West 10th Avenue
    Vancouver, BC V5Z 1L3

    Affiliate Websites
    Research Areas
    • Gene expression
    • Signal transduction
    • Pediatric cancers
    Summary

    Most chemotherapeutic agents used to treat childhood malignant tumours target the cellular machinery involved in replicating the DNA of rapidly dividing cells. However, these agents do not distinguish malignant from normal proliferating cells, and therefore may damage the growing child's development. Increasing our understanding of how tumour cells respond to the signals, from outside or within the cell, that tell it to divide or not will give us insights into the pathways specific to tumour cells. Studying these pathways, collectively known as cellular signal transduction pathways, is central to understanding tumour cell biology. Targeting these pathways can be used as a treatment strategy, while minimizing effects on normal growth. The focus of my research group is the investigation of how gene rearrangements or mutations disrupt signal transduction in pediatric malignant tumours, or how genome-wide changes in gene expression relate to signalling alterations in these tumours. The ultimate goal is to identify new therapeutic targets in childhood cancer.

    Current Projects

    While a number of the proteins involved in signal transduction pathways have been targeted in adult cancers, little attention has been paid to childhood cancer. One difficulty has been deciding which pathways to target. We have had past success analyzing genetic alterations in childhood cancers. In contrast to most adult malignant tumours, which appear to have complex genetic etiologies, many solid childhood tumours show recurrent chromosomal rearrangements called translocations. We have found that a number of these translocations disrupt key genes regulating signal transduction pathways. In this way, we have been able to single out those pathways that might be de-regulated in particular childhood cancers, therefore potentially increasing the pace of new therapeutic target discoveries.

    Current projects include:

    Cyclin D1 regulation in pediatric solid tumours
    The abundance of cyclin D1 is rate-limiting in G1 phase progression. The group has found, by microarray and other studies, that several pediatric sarcoma translocation-associated fusion oncoproteins markedly up-regulate cyclin D1 expression. The mechanism of over-expression is currently being assessed by studying transcriptional regulation (such as by the AP-1 and NFKB transcription factors), regulation by the generation of reactive oxygen species (ROS), and regulation of cyclin D1 protein stability by the PI3-kinase-AKT pathway.

    Role of the insulin-like growth factor 1 receptor (IGFRI) pathway in pediatric neoplasia
    IGFs are expressed in many pediatric malignancies, and it is thought that the IGFRI axis plays a key role in oncogenesis in these tumours. The group recently found that the ETV6-NTRK3 (EN) fusion protein fails to transform IGFRI -/- murine fibroblasts, but that re-introduction of IGFRI restores EN transformation activity. Ongoing studies are assessing mechanisms by which IGFRI complements dominantly acting fusion proteins.

    Role of transforming growth factor beta (TGFß) in pediatric neoplasia
    One of the hallmarks of advanced malignancies is the production by tumour cells of TGFß and, paradoxically, the inhibition of TGFß signaling in tumour cells. The group has found through microarray studies that TGFß is markedly up-regulated by the EN protein, and that EN inhibits TGFß signaling. Therefore EN transformation appears to an excellent model of the role TGFß in neoplasia.

    Role of integrin-linked kinase (ILK) and other adhesion molecules in tumour spheroid growth and survival
    The group recently adapted the growth of tumour cell lines as multicellular spheroids as an alternative culturing method in vitro. They found that spheroid cultures show a marked increase in resistance to apoptosis, and that this appears to involve integrin-linked kinase (ILK), an activator of AKT. They hypothesize that cell-cell adhesion through fibronectin activates an ILK-AKT survival pathway in these cells. Recent studies have also implicated the cadherin family of surface molecules as additional players in this process.

    Alteration of a novel E3 ligase in Wilms' tumour
    The group recently cloned the 6q21 breakpoint of a t(6;15) translocation in Wilms' tumour (WT), the most common pediatric renal malignancy. They found that it disrupts expression of a novel E3 ligase, which they called WT-ANK. Expression was reduced in 18/25 WT compared to matched normal kidneys. E3 ligases are involved in targeting proteins for proteasomal degradation, and current studies are focused on the biology of WT-ANK.

    Selected Publications
    Davicioni E, Anderson MJ, Finckenstein FG, Lynch JC, Qualman SJ, Shimada H, Schofield DE, Buckley JD, Meyer WH, Sorensen PH, Triche TJ.: Molecular classification of rhabdomyosarcoma--genotypic and phenotypic determinants of diagnosis: a report from the Children's Oncology Group. Am J Pathol. 2009 Feb;174(2):550-64.

    Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk N, Mathers J, Becker L, Carneiro F, MacPherson N, Horsman D, Poremba C and Sorensen PHB. Expression of the ETV6-NTRK3 gene fusion as a primary event in secretory breast carcinoma. Cancer Cell 2:367-76, 2002

    Sorensen, PHB, Lynch, JC, Qualman, SJ, Tirabosco, R, Lim, JF, Maurer, H, Crist, W, Bridge, J, Triche, TJ, and Barr, FG. PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the Children's Oncology Group. J Clin Oncol 11:2672-9, 2002.

    Morrison, KB, Tognon, CE, Garnett, MJ, Deal, C, and Sorensen, PHB. ETV6-NTRK3 transformation requires insulin-like growth factor 1 receptor signaling and is associated with constitutive IRS-1 tyrosine phosphorylation. Oncogene 21:5684-5695, 2002.

    Lawlor, ER, Scheel, C, Irving, J, and Sorensen, PHB. Anchorage independent growth signaling in Ewing tumor cells differs from signaling in adherent monolayers. Oncogene 21:307-18, 2002.

    Tognon C, Garnett M, Kenward E, Kay R, Morrison K, Sorensen, PHB. The chimeric protein tyrosine kinase ETV6-NTRK3 requires both Ras-Erk1/2 and P13-Kinase-Akt signaling for fibroblast transformation. Cancer Research 61: 8909-16, 2001.

    Bourgeois, JM, Knezevich, SR, Mathers, JA, and Sorensen, PHB. Molecular detection of the ETV6-NTRK3 gene fusion differentiates congenital fibrosarcoma from other childhood spindle cell tumours. Amer J Surg Path 24:937-946, 2000

    Knezevich, SR, McFadden, DE, Tao, W, Lim, JF, and Sorensen, PHB. Identification of a novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nature Genetics 18: 184-187, 1998.

    Lawlor, ER, Mathers, JA, Bainbridge, T, Horsman, DE, Kawai, A, Healey, JH, Huvos, AG, Bridge, JA, Ladanyi, M, and Sorensen, PHB. Peripheral primitive neuroectodermal tumours in adults: documentation by molecular analysis. J Clin Oncol 16:1150-1157, 1998.

    Sorensen, PHB, Chen, C-S, Smith, FO, Arthur, DC, Bernstein, ID, Domer, PH, Korsmeyer, SJ, Hammond, GD, and Kersey, JH. Molecular rearrangements of the MLL gene are present in most cases of infant AML and are strongly correlated with monocytic or myelomonocytic phenotypes. J Clin Invest 93: 429-437, 1994.

    Sorensen, PHB, Lessnick, SL, Lopez-Terrada, D, Liu, XF, Triche, TJ, and Denny, CT. A second Ewing's Sarcoma translocation, t(21;22), fuses the EWS gene to another ETS-family transcription factor, ERG. Nature Genetics 6: 146-151, 1994.

    Grants
    Honours & Awards

    UBC Pathology Award for Excellence in Research and Discovery - 2014
    UBC Pathology Award for Excellence in Research and Discovery - 2001
    Johal Endowed Chair in Pediatric Oncology, Basic and Translational Research, University of BC - 1999
    Childhood Cancer Group Young Investigator Award, National Childhood Cancer Foundation (US) - 1999 
    Young Investigator Award - Society for Pediatric Pathology - 1996
    Lotte Strauss Award - Under Age 40 Research Award, Society for Pediatric Pathology - 1994
    British Columbia Laboratory Physicians Prize in Pathology, Graduating Medical School Class, UBC - 1984

    Awards for Scholarship
    Centennial Fellowship - Medical Research Council of Canada - 1991-93
    Fellowship - Medical Research Council of Canada - 1984-88
    University of British Columbia Scholarship Fund - 1983
    University of British Columbia Summer Research Competition (Winner of Undergraduate Medicine Division) - 1982
    Epidemiology Award, Undergraduate Medicine, McGill University (Top Mark in Epidemiology & Statistics) - 1981
    Dean's Honour Role Graduating Class, University of British Columbia - 1980
    Society of Chemical Industry Merit Award (Gold Medal, Outstanding Graduating Student in Biochemistry, University of British Columbia) - 1980
    William Skelly Kinsmen Award (Cystic Fibrosis Summer Research Prize-Top Undergraduate Student in Canada) - 1979
    University Scholarship (Top 5% of Faculty of Science, University of British Columbia) - 1979
    Research Group Members
    • Michelle Pollard - Lab manager
    • Terry Pape - Technician
    • Amal El Negger - PhD student
    • Adi Barokas - Technician
    • Amy Li - Technician
    • Barak Rotblat - Postdoctoral Fellow
    • Cristina Tognan - Research Scientist
    • Gabriel Leprivier - Postdoctoral Fellow
    • Genny Trigo - Technician
    • Joan Mathers - Technician
    • Naniye Cetinbas - PhD student
    • Paul Clarkson - Masters student
    • Tony Ng - PhD student