Arun Seth

Dr Seth is a full Professor of Laboratory Medicine and Pathobiology at the University of Toronto, supervising graduate students, postdoctoral fellows, summer students, and medical residents.

Cross-appointed as a full Professor in the U of T Faculty of Dentistry, he is also an Adjunct Professor of Medicine for the Medical University of South Carolina.

Dr Seth created, and is director of, the Sunnybrook Genomics Core Facility, conducting state-of-the-art molecular analysis and research. As director of the Sunnybrook Molecular Diagnostics laboratory he provides molecular diagnostic tests for the departments of Clinical and Anatomical Pathology, as well as the department of Microbiology.

Other appointments at Sunnybrook Research Institute include, Senior Scientist, Member of the Breast Cancer Research Centre, and Co-chair of the Access to Data and Tissue Committee.

He provides collaborative and consultative support for staff pathologists, oncologists, and surgeons and maintains national and international research programs with other scientists.

A productive and respected senior scientist, he has authored nearly 200 peer-reviewed papers and book chapters.

As a Group Leader and then Tenured Staff Scientist at the US National Institutes of Health he led a major breast cancer genome anatomy project in the National Cancer Institute’s Laboratory of Molecular Oncology designed to identify molecular targets that have diagnostic and therapeutic applications.

Continuation of that work at the University of Toronto led to the characterization of novel genes associated with breast tumors and angiogenesis.

His team has created a clinically relevant patient-derived tumor xenograft model in which primary breast tumor specimens are transplanted directly into NOD/SCID mice to observe their growth and metastatic behavior in vivo.

Recently, by whole miRNome analysis his team has identified a panel of five microRNAs that predicts patients who have a high chance of developing prostate cancer recurrence and metastasis at the time of surgical treatment.

He serves on Department of Defense, NIH, CIHR, CBCF and CCSRI grant review panels.

Founding Editor-in- Chief for the journal “Cancer Genomics and Proteomics”, he was an Associate Editor for “Cancer Research” and serves on the editorial boards of four other cancer related international journals.

Organizing and participating in scientific conferences is an essential part of his service, most recently as an organizing committee member for the 9th International Conference of Anticancer Research, 2014 in Sithonia, Greece.

He has been a board member of Oncostasis Inc. (California) and on the advisory board of Quantum Biotechnologies (Montreal).

His laboratory uses a wide range of molecular and cellular biology technologies, including high throughput next generation sequencing and transgenic and knockout mouse models of human cancers. These technologies have the potential to serve as powerful diagnostic/prognostic tools for personalized medicine.

Research Synopsis

The research team

The team is multidisciplinary, combining expertise in patient care, translational and clinical research in breast and prostate cancers, with molecular pathogenesis of cancer, and biostatistics.

The team includes world-class recognized experts from major Toronto institutions: Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University Health Network and the University of Toronto.

The team brings access to multiple mouse models of breast/prostate cancer metastasis, thousands of archived breast/prostate tissues and accompanying clinical data, as well as a prospective cohort of cancer patients.

Functional biology

Over the past decade, our laboratory has focused on studying molecular targets that have diagnostic and therapeutic applications. We have isolated a number of genes that are associated with progression of breast and prostate cancer.

Our laboratory uses molecular technologies identify cell-signaling pathways affected by targeted gene manipulation at the level of mRNA and microRNA. Biological effects of that manipulation are observed using a wide range of molecular and cellular biology assays.

Next-generation DNA/RNA sequencing, including high throughput next generation systems (ABI SOLiD and ION Torrent PGM) are used by us for whole transcriptome analysis, de novo sequencing, microRNA analysis, SNP discovery, and whole and targeted genome re-sequencing, among others.

Additional research avenues are followed using tissue microarrays, real-time PCR, digital PCR, transgenic and knockout mouse models of human cancers. We developed a human bone NOD/SCID mouse model wherein xenografted human bone provides a humanized environment for a range of human cancer cells. For example, we use patient derived primary tumors in that model to observe their growth and metastatic behavior in vivo.

Molecular diagnostics

Our laboratory also plans and conducts diagnostic tests for the departments of Clinical and Anatomical Pathology using state-of-the-art methods and equipment.

Each assay meets the rigorous validation standards of the Ontario Laboratory Accreditation system.

We have a mandate to automate and streamline lab processes so that the potential for error is minimized and detected if it occurs. Sample testing and liquid handling is automated wherever possible to ensure efficient and accurate results and error detection. The existing menu includes tests for lymphomas, genetic diseases, infectious diseases and solid tumors.

In addition to routine assays we conduct research aimed at discovering and developing new sensitive and specific molecular diagnostic tests utilizing novel methods and next generation technologies. 

A Microsatellite Instability (MSI) test was developed for five regions (Bat-25, Bat-26, D5S346, D173250 and D2S123) known to significantly affect the course of colorectal cancer. These markers have been proven capable of detecting MSI sensitively and specifically, and are recommended as the first-choice panel for defining MSI status by the American Joint Commission on Cancer.

We are using PCR/Fragment Analysis by ABI Genetic Analyzer to diagnose lymphomas using the BIOMED-2 protocol.

We use immunoglobulin heavy chain (IgH) gene rearrangement and T-cell receptor (TCR) gene rearrangement for B/T-cell lymphomas. Clonality of B-Cell is determined by VDJ/IgH gene rearrangement. TCR-is used to assess clonality of T-cell as is TCR- of t(14;18) translocation for follicular lymphoma (BCL2 gene rearrangement,- major breakpoint region (MBR) located in the 3’UTR of BCL2 gene) & - minor cluster region (MCR)); and detection of BCL1-1/JH t(11;14) chromosomal translocation is also routinely done for Mantle Cell Lymphomas are done by PCR and gel analysis. 

The Cobas 4800 system from ROCHE is used for qPCR to detect BRAFV600E, CT/NG, HPV, C. difficile, HSV1/2 and MRSA/MSSA. A fully automated system, it provides complete sample preparation, amplification and detection of specific targets from human samples. Our current Cobas 4800 system menu includes: qualitative detection of Chlamydia trachomatis (CT) and/or Neisseria gonorrhoeae (NG) in patient specimens and simultaneous detection of 14 high-risk HPV types and specific genotyping information for HPV Type 16 and 18.

Fluorescence Resonance Energy Transfer (FRET) based Invader™ Technology developed by Third Wave is employed to test single base pair changes in patient DNA samples.

Our menu includes the Thrombophilia Panel: Factor V Leiden (FVL), Factor II (Prothrombin) Variant (FIIV), Methylene TetraHydroFolate Reductase (MTHFR).

We also test for three mutations (C282Y, H63D, and S65C) in the hemochromatosis (HFE) gene that causes Hereditary Hemochromatosis (HH).

We also test for three mutations in the thiopurine S- methyltransferase (TPMT) gene on chromosome 6 (G460A, G238C and A719G) that account for approximately 75 – 85% of phenotypic TPMT deficiencies. 

In addition to providing a broad menu of molecular diagnostic tests, we conduct research aimed at applying new technologies to create wide range of more sensitive and specific tests.

Our laboratory is continuously working out new protocols to stay current as well as advance the science of molecular pathology utilizing novel methods and next generation technologies.

The ability to identify causal mutations and deliver a genetic diagnosis is the primary goal of personalized diagnostics.

The next generation DNA sequence technology is mature enough to be used in the molecular diagnostic laboratories.

Our “Ion Torrent Personal Genome Machine” is an essential tool for that work. When combined with our in-house access to patients and their tumors, we hope to bring personalized medicine to patients at Sunnybrook.

Research foci

Cancer biomarkers

Molecular investigation of variations in the incidence of cancer in diverse regions and populations bearing unique genetic mutations has made it clear that different cancers have separate and distinct mutations that underlie clinical similarities.

Our laboratory can rapidly screen samples for somatically acquired mutations found in human cancers that have known biological functions.

Panels of known mutations with strong clinical significance are used to classify patient tumors for individualized prediction of outcome and treatment decisions.

Family histories and DNA/RNA samples from affected and unaffected families are essential to linking specific genetic changes to clinical disease.

We apply these cancer gene panels for Canadian breast and thyroid cancer patients, as well as tumor samples from collaborators around the world.

Prostate cancer biomarkers

MicroRNA (miRNA) markers are increasingly important as independent prognostic markers for prostate cancer progression or recurrence after surgical treatment.

We are searching for miRNAs that distinguish between patients with lethal or indolent disease in order to improve how patients are selected for treatment. Some miRNAs are already known to be associated with aggressive forms of prostate cancer that develop and progress to metastasis.

When those microRNAs are detected at an early stage in prostate cancer they become a screening tool for early stage prostate cancer.

We used whole genome analysis of microRNA expression in tumors from patient groups with lymph node metastasis or recurrence after radical prostatectomy. Early results have yielded a novel panel of five miRNAs that is predictive of which patients will develop recurrent prostate cancer after surgical treatment.

With functional testing we found that ectopic expression of two of those miRNAs in prostate cancer cell lines enhanced motility and invasiveness, suggesting direct involvement in metastatic progression. Effects of overexpressing those miRNAs on tumor development are being investigated in our NOD/SCID mouse xenograft model of human prostate cancer. 

Extension of this analysis to biopsy samples is underway, providing a less invasive option for monitoring of prostate cancer in patients.

Prostate cancer therapy

A second avenue of investigation is testing ETS gene translocations as biomarkers of prostate cancer and potential therapeutic targets.

In some prostate cancers, we have identified that part of the TMPRSS2 gene that is normally activated by androgen is translocated upstream of a cancer related ERG gene. Thus the resulting TMPRSS2:ERG fusion gene becomes abnormally active in response to androgen, but only in prostate cancer not in benign tissue. It is therefore a potential marker of malignancy.

Our future research is designed to test whether screening for this gene in patient blood and tumor samples could predict progression and metastasis of prostate cancer that will be of great utility in aiding clinical management for cancer patients.

We have been investigating the status of TMPRSS2:ERG fusion and associated target genes, whose expression is dysregulated in many prostate cancers.

We characterized an ERG specific antibody and used it to show, perhaps for the first time, that ERG protein is in fact expressed from the ERG fusion mRNA.

This is a key clinical testing breakthrough demonstrating that immunohistochemistry can be used to detect ERG overexpression in archived tumor samples.

miRNAs are effective regulators of gene expression that have a significant role in the pathogenesis of prostate and various other cancers. A high prevalence of aberrant miRNA expression in prostate cancer suggests they can be used as biomarkers and next generation of molecular anticancer therapeutics.

Characterizing mechanisms by which miRNAs control the translation of androgen induced ERG overexpression is currently done in our lab.

We have already identified several miRNAs that interact with the 3′UTR of the ERG mRNA, likely affecting its expression in prostate tumors.

Candidate miRNAs that reduce ERG expression are being tested in our mouse model of human prostate cancer in order to regress or eliminate xenografted tumors.

Breast cancer therapy

One of our goals is to develop new therapeutics for treatment and cure of molecularly defined subsets of breast cancer.

A current focus of that work is on recombinant IGFBP7 protein as candidate for preclinical testing.

A member of the insulin-like growth factor binding protein family, we have studied IGFBP7 in breast cancer for many years, finding it to be expressed at high levels in benign breast tumors, and that patients with high levels of IGFBP7 in their tumors have a better prognosis. 

Recent Publications

Y. Amemiya, W. Yang, T. Benatar, S. Nofech-Mozes, A. Yee, H. Kahn, C. Holloway, and A. Seth. IGFBP7 reduces growth and migration of human breast cancer cells in vitro and in xenografted tumors in vivo. Breast Cancer Res Treat. 2011 Apr;126(2):373-84.

Qi Long, Brent A. Johnson, Adeboye O. Osunkoya, Yu-Heng Lai, Wei Zhou, Mark Abramovitz, Mingjing Xia, Mark Bouzyk, Robert Nam, Linda Sugar, Aleksandra Stanimirovic, Brian R. Leyland-Jones, Arun K. Seth, John A. Petros, and Carlos S. Moreno. Protein-coding and MicroRNA Biomarkers of Recurrence of Prostate Cancer Following Radical Prostatectomy, American Journal of Pathology 2011 Jul;179(1):46-54.

Haley Buff Lindner, Aiguo Zhang, Juanita Eldridge, Marina Demcheva, Philip Tsichilis, Arun Seth, John Vournakis and Robin C. Muise-Helmericks. Anti-bacterial effects of Poly-N- Acetylglucosamine Nanofibers in Cutaneous Wound Healing: Requirement for AKT1. PLoS ONE, 2011 Apr 29;6(4):e18996.

Robin C. Muise-Helmericks, Marina Demcheva, John N. Vournakis and  Arun Seth. Poly-N- Acetylglucosamine Fibers Activate Bone Regeneration in a Rabbit Femur Injury Model, The Journal of Trauma. 2011 Aug;71(2 Suppl 1):S194-6.

Stephanie Bacopulos, Yutaka Amemiya, Judit Zubovits, Angelika Burger and Arun K. Seth.  Effects of Partner Proteins on BCA2 RING Ligase Activity, BMC Cancer. 2012 Feb 8;12(1):63.

Aida Gordanpour, Robert Nam, Linda Sugar and Arun Seth, MicroRNAs and Gene Fusions in Prostate Cancer: from Biomarkers to Molecularly-based Therapeutics. Prostate Cancer and Prostatic Diseases, 2012 Feb 14. doi: 10.1038/pcan.

Tania Benatar, Wenyi Yang, Yutaka Amemiya, Valentina Evdokimova, Harriette Kahn, Claire Holloway, Arun Seth. IGFBP7 Reduces Breast Tumor Growth by Induction of Senescence and Apoptosis Pathways. Breast Cancer Res Treat. 2012 Jun;133(2):563-73.

Du WW, Fang L, Yang W, Sheng W, Zhang Y, Seth A, Yang B, Yee A., The role of versican G3 domain in regulating breast cancer cell motility including effects on osteoblast cell growth and differentiation in vitro evaluation towards understanding breast cancer cell bone metastasis. BMC Cancer. 2012 Aug 3;12 (1):341.

Ehsani L, Seth R, Bacopulos S, Seth A, Osunkoya AO, BCA2 is differentially expressed in renal oncoytoma:  an analysis of 158 renal neoplasms. Tumour Biol. 2012 Dec. 15.

Evdokimova V, Tognon CE, Benatar T, Yang W, Krutikov K, Pollak M, Sorensen PH, Seth A.  IGFBP7 binds to the IGF-1 receptor and blocks its activation by insulin-like growth factors. Science Signaling. 2012 Dec 18; 5 (255): ra92

Chatterjee S, Bacopulos S, Yang W, Amemiya Y, Spyropoulos D, Raouf A, and Seth A, Igfbp7 Controls the Balance Between Luminal Progenitor Cell Expansion and differentiation During Pregnancy and Lactation. PLoS One. 2014 Feb 4;9(2):e87858. doi: 10.137

Qi Long, Jianpeng, Adeboye O. Osunkoya, Soma Sannigrahi, Brent A. Johnson, Wei Zhou, Theresa Gillespie, Jong Y. Park, Robert K. Nam, Linda Sugar, Aleksandra Stanimirovic, Arun K. Seth, John A. Petros, and Carlos S. Moreno. Global Transcriptome Sequencing of Formalin- Fixed Patient Samples Identifies Biomarkers of Recurrence in Prostate Cancer. Cancer Research Jun 15;74(12):3228-37, 2014

Y. Amemiya, S. Bacopulos, M. Al-Shawarby, D. Al-Tamimi, W. Naser, M. Khalifa, E. Slodkowska, Seth. A Comparative Analysis of Breast and Ovarian Cancer Related Gene Mutations in Canadian and Saudi Arabian Breast Cancer Patients. Anticancer Res. 2015 May;35(5):2601-10.

Robert K. Nam, Yutaka Amemiya, Tania Benatar, Jessica Stojcic-Bendavid, Stephanie Bacopulos, Christopher Sherman, Linda Sugar, Wenyi Yang,  Aiguo Zhang, Laurence Klotz, Steven A. Narod, and Arun Seth. Identification of a Five MicroRNA Signature for Prostate Cancer Recurrence and Metastasis from Whole miRNome Analysis. J Cancer. Sep 15;6(11):1160-71

Nam RK, Benatar T, Wallis CJ, Amemiya Y, Yang W, Garbens A, Naeim M, Sherman C, Sugar L, Seth A. MiR-301a regulates E-cadherin expression and is predictive of prostate cancer recurrence. Prostate. 2016 Mar 15. doi: 10.1002/pros.23177.

Appointments

Director, Sunnybrook Genomics Core Facility