Mathieu Lupien

Picture of Dr. Mathieu Lupien

Associate Professor

Ph.D., McGill University

Ontario Cancer Institute / University Health Network
The MaRS Centre
Toronto Medical Discovery Tower
101 College Street, 11-706
Toronto, ON M5G 1L7

Email to Dr. Mathieu Lupien

At A Glance

  • Research in the Lupien lab focuses on the Epigenetics of cancer, with an emphasis on comprehensive data analytics and mid to high-throughput biological assays.
  • The laboratory provides a unique environment where both wet laboratory scientists and computational biologists thrive.
  • Data generation relies on next-generation sequencing based assays and new mid to high-throughput profiling technologies
  • Data analytics relies on existing software and on in-house algorithmic and software development 

 

Short Bio

Dr. Mathieu Lupien has been a scientist at the Princess Margaret Cancer Centre since 2012 and is an assistant professor in the Department of Medical Biophysics at the University of Toronto. He also has a cross-appointment with the Ontario Institute for Cancer Research (OICR). He earned his Ph.D. at McGill University (Montreal, Canada) in 2005, followed by post-doctoral training in medical oncology at the Dana-Farber Cancer Institute, Harvard Medical School (Boston, MA) as an Era of Hope fellow. Dr. Lupien completed his post-doctoral training in 2008 and was recruited as a faculty member at the Dartmouth Medical School (Hanover, NH) in 2009, where he became Director of the Quantitative Epigenomics Laboratory. Dr. Lupien has co-authored numerous peer-reviewed publications, including seminal work reported in high-impact journals including Science, Cell, Nature Genetics and The Journal of the National Cancer Institute. Among other honours, Dr. Lupien is a recipient of the Young Investigator Award from the OICR, the New Investigator Salary Award from CIHR, The Rising Star in Prostate Cancer Research award from PCC/Movember and the Till and McCulloch Discovery of the Year award.

 

The Three-Dimensional Genome and Epigenetics basis of Cancer: From Genes and Beyond

Our genome consists of 6 billion “letters” of DNA sequence that form “words” of different nature, such as "nouns" (genes), "verbs" (promoters) and "adjectives" (enhancers) [1, 2]. These need to be organized into “sentences” to give rise to any particular “story”. Muscle, brain, bone and all other cells each emerge from unique "stories". The order of the letters does not typically change across different cell types. The key to generate muscle versus brain or other cell types is to fold our genome differently in each cell to re-align words and thereby create distinct sentences giving rise to unique stories. In the process, some words are masked and therefore no longer part of the story. This folding process is guided by epigenetic events, literally events above (epi) our genome (genetics), that act like post-it notes to bookmark the regions of our genome that need to be read and those that are to be masked in any particular cell type.

Disease development commonly stems from changes in the story of normal cells. Mutations or genetic variations will change the letters or words of a normal story to promote cancer development. Genetic profiling has identified a large collection of mutations and genetic predispositions to cancer. However, the words they target and thereby the underlying biological mechanisms affected in cancer are for the most part unknown.

One research project led by the Lupien Lab consists of delineating the functional consequence of mutations and genetic predispositions in cancer by identifying the words they target and determining the story of cancer cells. This is possible by mapping epigenetic events that discriminate the different words of the human genome. Epigenetic events correspond to the cosmetic changes applied to the human genome. They are chemical modifications that regulate word masking and genome "folding". Different epigenetic events can discriminate out nouns from verbs and adjectives that are readable or masked across the genome. Based on this, the Lupien Lab recently mapped a series of epigenetic events found on the genome of cancer cells to demonstrate that genetic predispositions to breast and prostate cancers were preferentially found in adjectives (enhancers) [1, 2]. These genetic alterations can modulate the function of these adjectives, changing their degree, thereby affecting expression of target oncogenes or tumor suppressor genes (the nouns) to promote cancer development. For instance a normal sentence such as “express more gene A” would be changed in cancer to “express less gene A”. We are currently applying this methodology to reveal the functional nature of mutations that accumulate in tumors throughout their development or as they acquire resistance to drug treatment.

In addition to genetic alterations (research theme 1), changes in the readability of “words” can alter stories to promote cancer development. This occurs through epigenetic events that will affect how the genome is folded or how particular "words" are masked.

A second research project in The Lupien Lab consists of mapping the epigenetic events discriminating the nature of “words” across cancer cell genomes. Through this approach the “stories” specific to cancer cells can be identified. This approach was recently applied in colorectal cancer where significant differences in the maps of epigenetic events specific to enhancers [3] (the adjectives) could be detected between normal colorectal crypt and cancer cells. This is also used to identify the mechanisms that promote cancer progression. Recent work from the Lupien Lab compared epigenetic maps from breast cancer cells responsive or resistant to hormonal (endocrine) therapy [4]. Results revealed significant differences in all types of “words” that were masked and readable between drug-responsive and resistant breast cancer cells. This revealed a “story” specific to hormonal therapy-resistant breast cancer cells indicative of the activation of the Notch pathway. In agreement, drugs against the Notch pathway could block the growth of hormonal therapy-resistant breast cancer cells. On-going research is expanding this work to clinical samples.

For more information, please visit http://pmgenomics.ca/lupienlab/

 

Graduate Students:

  • Ali Madani Tonekaboni (co-supervisor)
  • Parisa Mazrooei
  • Aislinn Treloar
  • Stanley Zhou

 

List of Key Publications:

Link to Pubmed Publications
  • Gallo M, Coutinho FJ, Vanner RJ, Gayden T, Mack SC, Murison A, Remke M, Li R, Takayama N, Desai K, Lee L, Lan X, Park NI, Barsyte-Lovejoy D, Smil D, Sturm D, Kushida MM, Head R, Cusimano MD, Bernstein M, Clarke ID, Dick JE, Pfister SM, Rich JN, Arrowsmith CH, Taylor MD, Jabado N, Bazett-Jones DP, Lupien M, Dirks PB. MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin. Cancer Cell. 2015 Nov 25. pii: S1535-6108(15)00382-7. doi: 10.1016/j.ccell.2015.10.005. [Epub ahead of print] PubMed PMID: 26626085.

  • Bailey SD, Zhang X, Desai K, Aid M, Corradin O, Cowper-Sal Lari R, Akhtar-Zaidi B, Scacheri PC, Haibe-Kains B, Lupien M. ZNF143 provides sequence specificity to secure chromatin interactions at gene promoters. Nat Commun. 2015 Feb 3;2:6186. doi: 10.1038/ncomms7186. PubMed PMID: 25645053; PubMed Central PMCID: PMC4431651.

  • Brocks D, Assenov Y, Minner S, Bogatyrova O, Simon R, Koop C, Oakes C, Zucknick M, Lipka DB, Weischenfeldt J, Feuerbach L, Cowper-Sal Lari R, Lupien M, Brors B, Korbel J, Schlomm T, Tanay A, Sauter G, Gerhäuser C, Plass C; ICGC Early Onset Prostate Cancer Project. Intratumor DNA methylation heterogeneity reflects clonal evolution in aggressive prostate cancer. Cell Rep. 2014 Aug 7;8(3):798-806. doi: 10.1016/j.celrep.2014.06.053. Epub 2014 Jul 24. PubMed PMID: 25066126.

  • Zhang X, Bailey SD, Lupien M. Laying a solid foundation for Manhattan--'setting the functional basis for the post-GWAS era'. Trends Genet. 2014 Apr;30(4):140-9. doi: 10.1016/j.tig.2014.02.006. Epub 2014 Mar 22. Review. PubMed PMID: 24661571; PubMed Central PMCID: PMC4026049.

  • Mack SC, Witt H, Piro RM, Gu L, Zuyderduyn S, Stütz AM, Wang X, Gallo M, Garzia L, Zayne K, Zhang X, Ramaswamy V, Jäger N, Jones DT, Sill M, Pugh TJ, Ryzhova M, Wani KM, Shih DJ, Head R, Remke M, Bailey SD, Zichner T, Faria CC, Barszczyk M, Stark S, Seker-Cin H, Hutter S, Johann P, Bender S, Hovestadt V, Tzaridis T, Dubuc AM, Northcott PA, Peacock J, Bertrand KC, Agnihotri S, Cavalli FM, Clarke I, Nethery-Brokx K, Creasy CL, Verma SK, Koster J, Wu X, Yao Y, Milde T, Sin-Chan P, Zuccaro J, Lau L, Pereira S, Castelo-Branco P, Hirst M, Marra MA, Roberts SS, Fults D, Massimi L, Cho YJ, Van Meter T, Grajkowska W, Lach B, Kulozik AE, von Deimling A, Witt O, Scherer SW, Fan X, Muraszko KM, Kool M, Pomeroy SL, Gupta N, Phillips J, Huang A, Tabori U, Hawkins C, Malkin D, Kongkham PN, Weiss WA, Jabado N, Rutka JT, Bouffet E, Korbel JO, Lupien M, Aldape KD, Bader GD, Eils R, Lichter P, Dirks PB, Pfister SM, Korshunov A, Taylor MD. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature. 2014 Feb 27;506(7489):445-50. doi: 10.1038/nature13108. Epub 2014 Feb 19. PubMed PMID: 24553142; PubMed Central PMCID: PMC4174313.

  • Magnani L, Stoeck A, Zhang X, Lánczky A, Mirabella AC, Wang TL, Gyorffy B, Lupien M. Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer. Proc Natl Acad Sci U S A. 2013 Apr 16;110(16):E1490-9. doi: 10.1073/pnas.1219992110. Epub 2013 Apr 1. PubMed PMID: 23576735; PubMed Central PMCID: PMC3631697.

  • Cowper-Sal lari R, Zhang X, Wright JB, Bailey SD, Cole MD, Eeckhoute J, Moore JH, Lupien M. Breast cancer risk-associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression. Nat Genet. 2012 Nov;44(11):1191-8. doi: 10.1038/ng.2416. Epub 2012 Sep 23. PubMed PMID: 23001124; PubMed Central PMCID: PMC3483423.

  • Zhang X, Cowper-Sal lari R, Bailey SD, Moore JH, Lupien M. Integrative functional genomics identifies an enhancer looping to the SOX9 gene disrupted by the 17q24.3 prostate cancer risk locus. Genome Res. 2012 Aug;22(8):1437-46. doi: 10.1101/gr.135665.111. Epub 2012 Jun 4. PubMed PMID: 22665440; PubMed Central PMCID: PMC3409257.

  • Akhtar-Zaidi B, Cowper-Sal-lari R, Corradin O, Saiakhova A, Bartels CF, Balasubramanian D, Myeroff L, Lutterbaugh J, Jarrar A, Kalady MF, Willis J, Moore JH, Tesar PJ, Laframboise T, Markowitz S, Lupien M, Scacheri PC. Epigenomic enhancer profiling defines a signature of colon cancer. Science. 2012 May 11;336(6082):736-9. doi: 10.1126/science.1217277. Epub 2012 Apr 12. PubMed PMID: 22499810; PubMed Central PMCID: PMC3711120.

  • Magnani L, Ballantyne EB, Zhang X, Lupien M. PBX1 genomic pioneer function drives ERα signaling underlying progression in breast cancer. PLoS Genet. 2011 Nov;7(11):e1002368. doi: 10.1371/journal.pgen.1002368. Epub 2011 Nov 17. PubMed PMID: 22125492; PubMed Central PMCID: PMC3219601.