Mathieu Lupien

Dr. Mathieu Lupien is a Senior Scientist at the Princess Margaret Cancer Centre and an Associate Professor in the Department of Medical Biophysics at the University of Toronto. He is cross-appointed to the Ontario Institute for Cancer Research (OICR). He earned his Ph.D. at McGill University (Montreal, Canada) in 2005, after which he pursued postdoctoral 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 postdoctoral 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 before moving to the Princess Margaret Cancer Centre in 2012. Dr. Lupien is recognized for three seminal discoveries, namely that epigenetic modifications on histones can discriminate cell type-specific noncoding gene regulatory elements; that epigenetic alterations at gene regulatory elements underlie cancer initiation and progression; and that noncoding genetic alterations promoting cancer development preferentially target gene regulatory elements. Among other honours, Dr. Lupien is a recipient of the 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 human genome consists of 6 billion "letters" of sequence. These form different "words" that need to be organized in the right order to make a "story". Each "story" gives rise to a particular cell type. Because each cell type consists of a different "story" our genome needs to be organized in many different ways to make the right story readable. Although the order of the "letters" in our genome is typically unchanged across cell types, different stories can be generated by folding our genome in such a way that the "words" for a particular "story" align. "Words" not required in a given cell type are typically masked. Disease development commonly stems from changes in the "story" of normal cells. For instance, mutations or genetic variations will change the "letters" or "words" of a normal "story" to promote cancer development. These genetic defects cannot readily be corrected and are often considered irreversible. Normal "stories" can also be changed to cancer "stories" by modulating the legibility of "words" without affecting their "letters". This occurs through epigenetic events that will affect how the genome is folded or how particular "words" are masked. This is not a static process. Specific drugs can alter epigenetic events, inferring that cancer "stories" can be rendered indolent. Dr. Lupien's research is centered on identifying the changes in "word" masking and genome folding that operate in cancer cells to reveal their underlying molecular biology. The ultimate goal is to develop new and improved strategies to hinder cancer development.

Two thematic objectives drive Dr. Lupien's leading-edge research. The first consists of delineating the functional consequence of mutations and genetic predispositions in cancer by identifying the "words" that are targeted by these genetic defects. Each "story" relies on "words" aligning to form "sentences". These "sentences" consist of "words" of different nature that correspond to different functional elements of the genome, such as "nouns" (genes), "verbs" (promoters) and "adjectives" (enhancers). Mapping epigenetic events discriminates "nouns" from "verbs" and "adjectives" that are legible or masked across the genome. Using this principle the Lupien lab recently demonstrated that genetic predispositions to breast and prostate cancers were preferentially found in regions on the genome that harbour enhancers (the "adjectives"). These genetic predispositions can modulate the degree of these "adjectives" thereby affecting expression of target oncogenes or tumour 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 tumours throughout their development or as they acquire resistance to drug treatment.

The second thematic objective focuses on identifying the alterations in genome legibility or folding occurring in the course of cancer development. This is achieved by comparing maps of epigenetic events from normal versus cancer cells. By focusing on epigenetic events that discriminate the nature of "words", the Lupien lab can identify the "stories" specific to cancer cells. This was recently applied to colorectal cancer where epigenetic mapping revealed significant differences in the enhancers ("adjectives") used in normal colorectal crypt versus cancer cells. This approach can also help identify the mechanisms that promote cancer progression. Recent work from the Lupien lab focused on breast cancer compared epigenetic maps from cancer cells responsive or resistant to hormonal (endocrine) therapy. Results revealed significant differences in all types of "words" that were masked and legible between drug responsive and resistant breast cancer cells. This revealed a "story" specific to hormonal therapy-resistant breast cancer cells that identified a pathway promoting resistance. Ongoing research is expanding this work to clinical samples.

Related Links

Oncotarget. 2016 Jul 6;
Samuel N, Wilson G, Said BI, Pan A, Deblois G, Fischer NW, Alexandrova R, Casallo G, Paton T, Lupien M, Gariepy J, Merico D, Hudson TJ, Malkin D
Cancer Res. 2016 Apr 25;
Bhat-Nakshatri P, Goswami CP, Badve S, Magnani L, Lupien M, Nakshatri H
Mol Cancer Res. 2016 May;14(5):470-81
Malorni L, Giuliano M, Migliaccio I, Wang T, Creighton CJ, Lupien M, Fu X, Hilsenbeck SG, Healy N, De Angelis C, Mazumdar A, Trivedi MV, Massarweh S, Gutierrez C, De Placido S, Jeselsohn R, Brown M, Brown PH, Osborne CK, Schiff R
Oncotarget. 2016 Mar 29;7(13):15772-86
Planello AC, Singhania R, Kron KJ, Bailey SD, Roulois D, Lupien M, Line SR, de Souza AP, De Carvalho DD
Bioinformatics. 2016 Apr 15;32(8):1244-6
Smirnov P, Safikhani Z, El-Hachem N, Wang D, She A, Olsen C, Freeman M, Selby H, Gendoo DM, Grossmann P, Beck AH, Aerts HJ, Lupien M, Goldenberg A, Haibe-Kains B
Cancer Cell. 2015 Dec 14;28(6):715-29
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,...
Nucleic Acids Res. 2015 Nov 16;43(20):9742-56
Brunelle M, Nordell Markovits A, Rodrigue S, Lupien M, Jacques PÉ, Gévry N
Oncotarget. 2015 Sep 8;6(26):21878-91
Magnani L, Patten DK, Nguyen VT, Hong SP, Steel JH, Patel N, Lombardo Y, Faronato M, Gomes AR, Woodley L, Page K, Guttery D, Primrose L, Fernandez Garcia D, Shaw J, Viola P, Green A, Nolan C, Ellis IO, Rakha EA, Shousha S, Lam EW, Győrffy B, Lupien M,...
Bioinformatics. 2015 Sep 15;31(18):3057-9
Bailey SD, Virtanen C, Haibe-Kains B, Lupien M
Genomics. 2015 Aug;106(2):96-106
Gendoo DM, Smirnov P, Lupien M, Haibe-Kains B

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Associate Professor, Department of Medical Biophysics, University of Toronto
Investigator II, Ontario Institute for Cancer Research