Dr. Mathieu Lupien is a scientist at the Princess Margaret Cancer Center and holds a cross-appointment with the Ontario Institute for Cancer Research (OICR). He earned his PhD at McGill University in 2005, followed by postdoctoral training in medical oncology at the Dana-Farber Cancer Institute, Harvard Medical School in Boston, Mass. as an Era of Hope fellow. Lupien completed his postdoctoral training in 2008. In 2009, Lupien was recruited as a faculty member to the Dartmouth Medical School, in Hanover, NH where he became Director of the Quantitative Epigenomics Laboratory. Lupien has co-authored numerous peer-reviewed publications, including seminal work reported in high-impact journals such as Science, Cell, Nature Genetics and The Journal of the National Cancer Institute. Among other honours, Lupien is a recipient of a Young Investigator Award from OICR.
The human genome consists of six 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. Since 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 change 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. Lupien’s research is centered on identifying the changes in “word” masking and genome folding that operate in cancer cells and to reveal their underlying molecular biology. The ultimate goal is to develop new and improved strategies to hinder cancer development.
Two thematic objectives drive 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 changes 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 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 detected. 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.
|2012 -||OICR Investigator II, Ontario Institute for Cancer Research (OICR).|
|2012 -||Assistant Professor, Department of Medical Biophysics, University of Toronto.|
|2012 -||Scientist, Ontario Cancer Institute.|
|2010 - 2012||Director, Quantitative Epigenomics Laboratory, Institute for Quantitative Biomedical Sciences, Dartmouth Medical School.|
|2009 - 2012||Assistant Professor, Department of Genetics, Norris Cotton Cancer Center , Dartmouth Medical School.|
|2009 - 2012||Member, Cancer Mechanisms Research Program, Norris Cotton Cancer Center, Dartmouth Medical School.|
|2009 - 2012||Member, Integrative Biology Committee, Norris Cotton Cancer Centre, .|
|2005 - 2008||Postdoctoral Fellow, Molecular Pathology, Harvard Medical School, Dana-Farber Cancer Institute .|
- Magnani L, Lupien M.
Chromatin and Epigenetic Determinants of Estrogen Receptor Alpha (ESR1) Signaling.
- Mol Cell Endocrinol. 2013 May 16. doi:pii: S0303-7207(13)00203-7.
- 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.
- 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.
- 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.
- 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.
- He HH, Meyer CA, Shin H, Bailey ST, Wei G, Wang Q, Zhang Y, Xu K, Ni M, Lupien M, Mieczkowski P, Lieb JD, Zhao K, Brown M, Liu XS
Nucleosome dynamics define transcriptional enhancers.
- Nat Genet 2010 Apr; 42(4):343-7
- Go to Nucleosome dynamics define transcriptional enhancers.
- Lupien M, Eeckhoute J, Meyer CA, Wang Q, Zhang Y, Li W, Carroll JS, Liu XS, Brown M
FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription.
- Cell 2008 Mar 21; 132(6):958-70
- Go to FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription.