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 is a Senior Scientist at the Princess Margaret Cancer Centre and a Professor at the University of Toronto, with a cross-appointment at the Ontario Institute for Cancer Research. He serves on both the Research Executive and the Research Council on Oncology at the Princess Margaret Cancer Centre and is Chair of the Genetics and Epigenetics Program.

Dr. Lupien’s research posits that cancer is fundamentally a disease of the chromatin—the complex of DNA and proteins. Through his research, Dr. Lupien shifts the focus beyond genetic mutations to understanding how chromatin variants are acquired and inherited in a Mendelian manner to disrupt normal cellular processes and promote oncogenesis. Among his key discoveries, Dr. Lupien discovered chromatin variants in cancer that affect gene expression. He also contributed to identifying pediatric ependymoma as the first example of a cancer driven solely by chromatin variants rather than genetic mutations. By integrating chromatin and genetic variants, Dr. Lupien’s unveiled new classes of cancer drivers within the non-coding genome, and their combined action in cancer. Finally, his research has demonstrated the value of epigenetic therapies targeting chromatin variants to treat aggressive cancers, such as breast, prostate, leukemia, and diverse brain tumours.

In recognition of his contributions, Dr. Lupien has received numerous honours, including the Allan Slaight Collaborator Award, the Mona Gauthier Award, and the Canadian Cancer Society Bernard and Francine Dorval Award for Excellence. He is a three-time recipient of the Investigator Award from the Ontario Institute for Cancer Research, a two-time recipient of the Till and McCulloch Discovery of the Year Award, and an elected Fellow of the Royal Society of Canada.

Dr. Lupien earned his PhD in Experimental Medicine at McGill University under the mentorship of Dr. Sylvie Mader. He completed postdoctoral training in Medical Oncology as an Era of Hope Fellow at the Dana-Farber Cancer Institute/Harvard Medical School under the guidance of Dr. Myles A. Brown, and pursued executive education (PLDA) at Harvard Business School. Dr. Lupien joined the Princess Margaret Cancer Centre and the University of Toronto in 2012.

Research Synopsis

A human consists of trillions of cells with different functions to form different tissues & organs. While genetic differences account for the phenotypic traits unique to individuals, cells from different tissues & organs isolated from one individual each carry a copy of the same genome, a sequence of 6 billion DNA base pairs. Cells across tissues & organs appear and function very differently from one another because each uses different sections of the 6 billion DNA base pairs they carry.

In cells, DNA is packaged with proteins to form chromatin. Chromatin ranges from being “compacted” to “accessible”, the latter associated with sections of the genome driving cell identity. Tissues & organs develop from gradual changes in chromatin accessibility occurring over different DNA base pairs in a stem cell that differentiates into one of many mature cell types. While some DNA base pairs fall in compacted chromatin, others will lie in accessible chromatin to serve as templates for biological functions. Along the way, changes to chromatin accessibility are bookmarked with hundreds of different chemical modifications, such as DNA methylation. These chemical modifications are commonly referred to as “epigenetic” marks. Different combinations of these epigenetic marks over sections of DNA define epigenetic states. Epigenetic states differ across accessible and compacted chromatin and provide information complementary to DNA sequences. DNA base pairs that transition between chromatin accessibility or epigenetic states over development correspond to chromatin variants. Identifying chromatin variants specific to a cell type can therefore identify the genetic basis of a cell’s phenotype.

Cancer is a disease of the chromatin because it arises when a patient’s normal cell acquires the wrong chromatin variants, such as when a normal cell loses control over which sections of the genome are in accessible versus compacted chromatin. Such chromatin variants can originate from inherited or acquired genetic variants, including risk-associated single nucleotide polymorphism (SNPs) or somatic mutations respectively. They can also originate from environmental stresses, such as metabolic stress. Cancer-specific chromatin variants reveal which misused DNA sequences contribute to oncogenesis. Understanding the nature of DNA sequences found in cancer-specific chromatin variants reveals genetic dependencies to oncogenesis and by extension the Achilles heel of cancer needed to guide precise treatment decisions. This is why our research is focused on chromatin and the epigenetics of cancer.

For more information, please visit the Lupien Lab website. 

Recent Publications

1. Xu X, Zhu H, Hugh-White R, Livingstone J, Eng S, Zeltser N, Wang Y, Pajdzik K, Chen S, Houlahan KE, Luo W, Liu S, Xu X, Sheng M, Guo WY, Arbet J, Song Y, Wang M, Zeng Y, Wang S, Zhu G, Gao T, Chen W, Ci X, Xu W, Xu K, Orain M, Picard V, Hovington H, Bergeron A, Lacombe L, Têtu B, Fradet Y, Lupien M, Wei GH, Koritzinsky M, Bristow RG, Fleshner NE, Wu X, Shao Y, He C, Berlin A, van der Kwast T, Leong H, Boutros PC, He HH. (2025). The landscape of N6-methyladenosine in localized primary prostate cancer. Nat Genet. 2025 Mar 24. doi: 10.1038/s41588-025-02128-y. 57(4):934-948. PMID: 40128621. Coauthor or Collaborator
2. Furlano K, Keshavarzian T, Biernath N, Fendler A, de Santis M, Weischenfeldt J, Lupien M. (2025). Epigenomics-guided precision oncology: Chromatin variants in prostate tumor evolution. Int J Cancer. doi: 10.1002/ijc.35327. PMID: 39853587. Senior Responsible Author
3. Laisné, M., Lupien, M. & Vallot, C. (2025). Epigenomic heterogeneity as a source of tumour evolution. Nat Rev Cancer. Jan;25(1):7-26. https://doi.org/10.1038/s41568-024-00757-9. PMID: 39414948. Senior Responsible Author
4. Zhang K, Wei J, Zhang S, Fei L, Guo L, Liu X, Ji Y, Chen W, Ciamponi FE, Chen W, Li M, Zhai J, Fu T, Massirer KB, Yu Y, Lupien M, Wei Y, Arrowsmith CH, Wu Q, Tan W. (2024). A chemical screen identifies PRMT5 as a therapeutic vulnerability for paclitaxel-resistant triple-negative breast cancer. Cell Chem Biol. 2024 Aug 21:S2451-9456(24)00323-4. doi: 10.1016/j.chembiol.2024.08.003. PMID: 39232499. Coauthor or Collaborator
5. Su P, Liu Y, Chen T, Xue Y, Zeng Y, Zhu G, Chen S, Teng M, Ci X, Guo M, He MY, Hao J, Chu V, Xu W, Wang S, Mehdipour P, Xu X, Marhon SA, Soares F, Pham NA, Wu BX, Her PH, Feng S, Alshamlan N, Khalil M, Krishnan R, Yu F, Chen C, Burrows F, Hakem R, Lupien M, Harding S, Lok BH, O'Brien C, Berlin A, De Carvalho DD, Brooks DG, Schramek D, Tsao MS, He HH. (2024). In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor-microenvironment interactions. Nat Genet. 2024 Sep 3. doi: 10.1038/s41588-024-01874-9. PMID: 39227744. Coauthor or Collaborator
6. Boutzen H, Murison A, Oriecuia A, Bansal S, Arlidge C, Wang JCY, Lupien M, Kaufmann KB, Dick JE. (2024). Identification of leukemia stem cell subsets with distinct transcriptional, epigenetic and functional properties. Leukemia. doi: 10.1038/s41375-024-02358-9. PMID: 39169113. Coauthor or Collaborator
7. Zhao SG, Bootsma M, Zhou S, Shrestha R, Moreno-Rodriguez T, Lundberg A, Pan C, Arlidge C, Hawley JR, Foye A, Weinstein AS, Sjöström M, Zhang M, Li H, Chesner LN, Rydzewski NR, Helzer KT, Shi Y; West Coast Dream Team Consortium; Lynch M, Dehm SM, Lang JM, Alumkal JJ, He HH, Wyatt AW, Aggarwal R, Zwart W, Small EJ, Quigley DA, Lupien M, Feng FY. (2024). Integrated analyses highlight interactions between the three-dimensional genome and DNA, RNA and epigenomic alterations in metastatic prostate cancer. Nat Genet. doi: 10.1038/s41588-024-01826-3. PMID: 39020220. Senior Responsible Author
8. Shrestha R, Chesner LN, Zhang M, Zhou S, Foye A, Lundberg A, Weinstein AS, Sjöström M, Zhu X, Moreno-Rodriguez T, Li H, West Coast Prostate Cancer Dream Team SC, Alumkal JJ, Aggarwal R, Small EJ, Lupien M, Quigley DA, Feng FY. (2024). An Atlas of Accessible Chromatin in Advanced Prostate Cancer Reveals the Epigenetic Evolution during Tumor Progression. Cancer Res. doi: 10.1158/0008-5472.CAN-24-0890. PMID: 38990734. Senior Responsible Author
9. Grillo G, Keshavarzian T, Linder S, Arlidge C, Mout L, Nand A, Teng M, Qamra A, Zhou S, Kron KJ, Murison A, Hawley JR, Fraser M, van der Kwast TH, Raj GV, He HH, Zwart W, Lupien M. (2023). Transposable elements are co-opted as oncogenic regulatory elements by lineage-specific transcription factors in prostate cancer. Cancer Discov. 2023 Nov 1;13(11):2470-2487. doi: 10.1158/2159-8290.CD-23-0331. PMID: 37694973. Senior Responsible Author.

Graduate Students

Shalini Bahl
Tina Keshavarzian
Chufan Zhang
Bei Qi Yan