Cancer
Genome Biology
At a glance
The genomics era opened the door to a new understanding of cancer. We now have a full view of the landscape of genomic alterations in cancer cells and which of them are responsible for driving disease progression. The challenge lies in determining how this information can be used optimally to achieve better outcomes for cancer patients. Therapeutically targeting cancer drivers requires a detailed mechanistic understanding of how the genes that either cause (oncogenes) or prevent cancer (tumour suppressor genes) work at the molecular, cellular, and whole organism levels. Beyond these genomic alterations, cancer is also driven by changes that affect the biology of the genome without altering the DNA sequence. These include changes in the structure and regulation of chromatin (the assembly of DNA and proteins within the nucleus of the cell that packages long DNA molecules into dense chromosomes), DNA damage and repair processes, and changes in gene expression (the process of converting genetic information into a functional product). Many of the inherited mutations and gene variants that determine susceptibility to cancer also affect these processes, and a better fundamental understanding of these inherited factors will lead to improved diagnostic and treatment strategies for those at risk.
The GCI is home to some of the world's most accomplished investigators focused on the mechanistic study of cancer drivers and the fundamental biology of the cancer genome. They include trailblazers who discovered and dissected the structures and functions of oncogenes decades before cancer genome sequencing projects. Their findings and the methodologies they established reshaped their fields and led to therapies that have had a major clinical impact. We now use our advanced capabilities in cancer modeling as well as molecular, cellular, and “-omics” analysis to reveal the regulatory and functional mechanisms of the cancer genome. With partners, we use the fundamental knowledge acquired through this research to inform drug development programs and improve the alignment of patients with existing treatment strategies.
Areas of Focus
Fundamental oncogene and tumour suppressor function. We use powerful genetic techniques to manipulate oncogenes and tumour suppressor genes in a wide range of cancer models, each with their own distinct strengths, including cell-based models, genetically engineered model organisms, and patient-derived models. This approach allows in-depth examination of how the products of these genes work at the molecular level and reveals their effects on cellular phenotypes (observable characteristics and behaviours resulting from gene expression and the environment), from behaviours that are hard-wired into the cancer cell to those that involve complex networks of interactions in the tumour microenvironment. By understanding how the products of genes implicated in cancer act at a mechanistic level, we build the foundations of precision medicine strategies that can target them.
Functional genomics to guide cancer therapy. The discovery of RNA-guided systems that precisely manipulate gene expression or edit genome sequences provided a powerful toolbox for functional genomics (the study of how genes and their products contribute to biological processes). This technology has taken us from examining one or a few genes at a time to “genome-wide” studies where all genes are interrogated simultaneously. Investigators at the GCI use the high-throughput tools of functional genomics to study cancer-relevant pathways and guide cancer therapy. We aim to identify genes and networks that modulate response to cancer drugs and to uncover genetic dependencies in cancer that can be exploited therapeutically. Importantly, some of the driving events discovered through cancer genome sequencing and other studies are not directly “actionable” – they cannot be targeted using current drug development technologies. Functional genomics allows large-scale probing of the genetic dependencies of these cancers, systematically targeting genes on a large scale to identify those where inhibition is selectively lethal to cancer cells harboring “undruggable” drivers. This approach, referred to as “synthetic lethality”, leads to promising strategies that can advance from the bench to the bedside through clinical trials involving the GCI’s collaborative precision medicine networks.
Chromatin biology and DNA repair. Epigenetics is a set of mechanisms that controls gene expression in a stable and heritable manner, without altering the DNA sequence. It encompasses chemical modifications of DNA and histones (the protein components of chromatin) and associated changes in the 3D structures of chromosomal regions. By controlling programs of gene expression, epigenetic mechanisms allow each of our vastly different cell types to develop their unique identities, even though they all contain the same genome. Other modifications to DNA result in damage, which must be repaired for cells to survive and avoid genomic changes that can initiate cancer. DNA damage can be caused by external factors, such as radiation and certain chemicals, and internal factors, including by-products of metabolism and DNA replication errors. The roles of chromatin biology and DNA repair in cancer are complex. Epigenetic changes during cancer development cause normal cellular identify to be lost and enable uncontrolled growth, metastasis, and therapeutic resistance. This can occur due to changes affecting the amounts or activities of protein complexes that “write”, “erase” and “read” chemical marks on DNA and histones or remodel chromatin structure, as well as certain classes of non-coding RNAs. These epigenetic regulators can be oncogenes or tumour suppressors, and some can be either, depending on cancer type. Likewise, some genes involved in DNA repair are well-known tumour suppressors that protect genomic integrity. However, cancer cells can experience large amounts of potentially lethal DNA damage, and DNA repair mechanisms can therefore also be genetic dependencies and drug targets. Knowing which chromatin regulators and DNA repair pathways are involved in a particular cancer type and whether they can be therapeutically targeted is a challenge. Research at the GCI aims to develop new treatment strategies by gaining molecular insight into the mechanisms of epigenetics and DNA repair. Using our unique pre-clinical modeling and advanced technology, we aim to understand cancer heterogeneity and how the complex processes affecting DNA and chromatin are involved in each subtype.
Nuclear receptors and control of gene expression. Many cancers respond to hormones (chemical messengers made by endocrine glands and transported to target cells in other tissues via the bloodstream) that regulate normal growth, development, reproduction, and metabolism, as well as being implicated in cancer. For example, the involvement of estrogen, a steroid hormone that controls the development and function of the female reproductive system, in many cases of breast cancer was known since the turn of the 20th century. GCI members were among the pioneering scientists who discovered nuclear receptors, proteins that bind to steroid hormones, thyroid hormones, certain vitamins and other molecules, and determined how they function as members of a class of proteins called transcription factors that bind to specific sites in the genome to control gene expression. The methods they devised during these ground-breaking studies became the gold standards in the field, used throughout academia and industry to study transcription factor function and identify natural and synthetic compounds targeting nuclear receptors. These discoveries led directly to revolutionary cancer treatments, including a cure for promyelocytic leukemia (PML), a previously lethal form of blood cancer. GCI scientists continue to explore the regulation and activities of nuclear receptors and other transcription factors involved in cancer. Our research uses innovative genetic and pharmacological studies in model organisms, including genetically engineered models replicating the genomic events that affect nuclear receptors in human tumours. We develop and apply unique cell-based models, genome-wide analysis of transcription factor binding and activity, and a range of other advanced molecular and cell biology techniques to understand these master regulators of gene expression and determine the best strategies to target them therapeutically.
Genetic susceptibility to cancer. The genetic and other changes that cause most cancers are due to a combination of chance events and the environment, rather than the genes we inherit from our parents. However, it is estimated that up to 10% of cancers can be linked to specific inherited genetic faults or variations. Some gene variants cause hereditary cancer syndromes, inherited diseases where affected individuals have a higher-than-average chance of developing certain cancers. Other genetic variants increase risk only marginally but can contribute to cancer development when unfavourable variants of several genes are inherited together. In addition to directly promoting the transformation of a normal cell into a cancer cell, hereditary factors can also raise the risk of developing cancer indirectly. For example, they may affect inflammatory and other processes linked to cancer initiation and progression. GCI investigators have developed sophisticated genetic techniques in model organisms to identify new genes that contribute to hereditary forms of cancer, including gene variants that primarily affect the immune system and the microenvironment, and identify promising strategies to treat tumours resulting from these genetic factors. Using genetic engineering, we model the effects of cancer-associated gene variants on tumour initiation and progression as well as normal development, which can provide vital clues to the nature of their cancer-causing activities. Our clinical and translational research networks allow us to derive models of hereditary cancers directly from patients, enabling us to use our screening approaches to find effective drugs or targets exploiting the phenomenon of synthetic lethality.
Team members
Our Discoveries
Researchers at the GCI made some of the earliest major discoveries on receptor tyrosine kinases (RTKs), a class of proteins implicated in many cancers. Activation of RTKs, typically by signals from the extracellular environment, controls powerful signaling pathways that instruct cells to grow and divide, move and invade local tissue, and survive in adverse conditions, among other things. Many RTKs are oncogenes, and some are important drug targets with clinically approved therapies that have dramatically improved outcomes in some cancer types. By discovering some of the major cancer-associated RTKs, establishing their oncogenic potential, and elucidating the molecular mechanisms by which they function, GCI researchers have been instrumental to these important advances.
Sequence of MET protooncogene cDNA has features characteristic of the tyrosine kinase family of growth-factor receptors. M Park, M Dean, K Kaul, MJ Braun, MA Gonda, G Vande Woude. Proceedings of the National Academy of Sciences 84 (18), 6379-6383, 1987
Mechanism of met oncogene activation. Park M, et al., Cell 45 (6), 895-904, 1986
Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming protein. Peschard P, et al., Molecular cell 8 (5), 995-1004, 2004
Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. WJ Muller, E Sinn, PK Pattengale, R Wallace, P Leder. Cell 54 (1), 105-115, 1988.
Elevated expression of activated forms of Neu/ErbB-2 and ErbB-3 are involved in the induction of mammary tumors in transgenic mice: implications for human breast cancer. PM Siegel, ED Ryan, RD Cardiff, WJ Muller. The EMBO journal 18 (8), 2149-2164, 1999.
An ErbB2 splice variant lacking exon 16 drives lung carcinoma. HW Smith, L Yang, C Ling, A Walsh, VD Martinez, J Boucher, D Zuo, et al., Proceedings of the National Academy of Sciences 117 (33), 20139-20148, 2020.
Phosphatases are classes of enzymes that remove phosphate groups from specific amino acids within proteins. They are crucial regulators of signaling pathways that influence all aspects of cellular behaviour. Several important phosphatases that target the amino acid phosphotyrosine were discovered by GCI scientists, and their research has been instrumental in defining the roles of these important proteins in normal physiology and disease. These important functions include regulation of insulin sensitivity and other key aspects of metabolism, breast cancer progression, therapy response in gastric cancer, and immune cell behaviour.
Cloning and characterization of a mouse cDNA encoding a cytoplasmic protein-tyrosine-phosphatase. B Mosinger Jr, U Tillmann, H Westphal, ML Tremblay. Proceedings of the National Academy of Sciences 89 (2), 499-503, 1992
Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. M Elchebly, et al. Science 283 (5407), 1544-1548, 1999
Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis. SG Julien, et al., Nature genetics 39 (3), 338-346, 2007
Dynamic reprogramming of signaling upon met inhibition reveals a mechanism of drug resistance in gastric cancer. Lai AZ, et al., Sci Signal. 2014 Apr 22;7(322):ra38. doi: 10.1126/scisignal.2004839.PMID: 24757178.
Impaired bone marrow microenvironment and immune function in T cell protein tyrosine phosphatase-deficient mice. You-Ten KE, Muise ES, Itié A, Michaliszyn E, Wagner J, Jothy S, Lapp WS, Tremblay ML. J Exp Med. 1997 Aug 29;186(5):683-93. doi: 10.1084/jem.186.5.683. PMID: 9271584
Repairing DNA damage is essential for normal cells to prevent the mutations involved in cancer development. However, tumour cells can also develop dependencies on DNA repair pathways to avoid lethal genome damage caused by metabolic and environmental factors associated with cancer progression. The genes involved in DNA repair therefore play a very complex role in cancer, with some being prominent tumour suppressor genes and others also having oncogenic features. Investigators at the GCI have discovered the roles of key proteins in specific DNA repair pathways and their involvement in cancer progression. GCI scientists have also done important work on uncovering the vulnerabilities of cancer cells that are deficient in specific DNA repair pathways, including pancreatic cancers that have mutations in the well-known tumour suppressor genes BRCA1 and BRCA2.
CUX1 stimulates APE1 enzymatic activity and increases the resistance of glioblastoma cells to the mono-alkylating agent temozolomide. Kaur S, Ramdzan ZM, Guiot MC, Li L, Leduy L, Ramotar D, Sabri S, Abdulkarim B, Nepveu A. Neuro Oncol. 2018 Mar 27;20(4):484-493. doi: 10.1093/neuonc/nox178. PMID: 29036362
CUX1 transcription factor is required for optimal ATM/ATR-mediated responses to DNA damage. Vadnais C, Davoudi S, Afshin M, Harada R, Dudley R, Clermont PL, Drobetsky E, Nepveu A. Nucleic Acids Res. 2012 May;40(10):4483-95. doi: 10.1093/nar/gks041. Epub 2012 Feb 8. PMID: 22319212
RAS transformation requires CUX1-dependent repair of oxidative DNA damage.
Ramdzan ZM, Vadnais C, Pal R, Vandal G, Cadieux C, Leduy L, Davoudi S, Hulea L, Yao L, Karnezis AN, Paquet M, Dankort D, Nepveu A. PLoS Biol. 2014 Mar 11;12(3):e1001807. doi: 10.1371/journal.pbio.1001807. eCollection 2014 Mar. PMID: 24618719
A Preclinical Trial and Molecularly Annotated Patient Cohort Identify Predictive Biomarkers in Homologous Recombination-deficient Pancreatic Cancer. Wang Y, et al. Clin Cancer Res. 2020 Oct 15;26(20):5462-5476. doi: 10.1158/1078-0432.CCR-20-1439.
Nuclear receptors are the major transducers of signals from steroid hormones, as well as some vitamins and other chemical mediators. In response to hormone binding and other signals, they enter the cell nucleus and bind to chromatin, directly influencing the activation and repression of specific sets of genes. GCI investigators were among the first to discover members of this important class of proteins and the first to show that some of them, referred to as “orphan” nuclear receptors, do not bind to any hormones or other naturally occurring substances, presenting unique opportunities for drug development. Further important contributions by GCI scientists include the discovery of unexpected interacting partners of the androgen receptor (AR), which is the major driver of prostate cancer, and novel genetically engineered models of breast cancers with activating mutations in the estrogen receptor (ER) that were recently discovered in patients.
Identification of a receptor for the morphogen retinoic acid. V Giguere, ES Ong, P Segui, RM Evans. Nature 330, 624-629
Identification of a new class of steroid hormone receptors. V Giguère, NA Yang, P Segui, RM Evans. Nature 331 (6151), 91-94
ERRα mediates metabolic adaptations driving lapatinib resistance in breast cancer. Deblois G, Smith HW, Tam IS, Gravel SP, Caron M, Savage P, Labbé DP, Bégin LR, Tremblay ML, Park M, Bourque G, St-Pierre J, Muller WJ, Giguère V. Nat Commun. 2016 Jul 12;7:12156. doi: 10.1038/ncomms12156. PMID: 27402251
Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer. Audet-Walsh É, Dufour CR, Yee T, Zouanat FZ, Yan M, Kalloghlian G, Vernier M, Caron M, Bourque G, Scarlata E, Hamel L, Brimo F, Aprikian AG, Lapointe J, Chevalier S, Giguère V. Genes Dev. 2017 Jun 15;31(12):1228-1242. doi: 10.1101/gad.299958.117. Epub 2017 Jul 19. PMID: 28724614
Point-activated ESR1Y541S has a dramatic effect on the development of sexually dimorphic organs. Simond AM, Ling C, Moore MJ, Condotta SA, Richer MJ, Muller WJ. Genes Dev. 2020 Oct 1;34(19-20):1304-1309. doi: 10.1101/gad.339424.120. Epub 2020 Sep 1. PMID: 32912899
Up to 10% of all cancers are caused by inherited genetic changes. However, while some inherited mutations are strongly associated with specific cancer types, the full spectrum of inherited factors that can affect cancer development is unknown. Predicting an individual’s risk can therefore be very challenging, even when there is a family history of cancer. GCI scientists are leaders in identifying the genetic and epigenetic changes associated with hereditary forms of aggressive cancers. Through innovative genetic studies in model organisms and analysis of patient samples, they have identified genes that are associated with inherited risk of cancer and created new ways to study the biology of cancers associated with known susceptibility genes. With partners, GCI investigators also lead major initiatives linking the laboratory and the clinic to improve our understanding of genetic risk factors for cancer.
Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer. Yan K, et al. Sci Adv. 2020 Jan 22;6(4):eaax0021. doi: 10.1126/sciadv.aax0021. eCollection 2020 Jan. PMID: 32010779
Smith AL, et al. Establishing a clinic-based pancreatic cancer and periampullary tumour research registry in Quebec. Curr Oncol. 2015 Apr;22(2):113-21. doi: 10.3747/co.22.2300. PMID: 25908910; PMCID: PMC4399608.
A region-based gene association study combined with a leave-one-out sensitivity analysis identifies SMG1 as a pancreatic cancer susceptibility gene. Wong C, et al. PLoS Genet. 2019 Aug 30;15(8):e1008344. doi: 10.1371/journal.pgen.1008344. PMID: 31469826
Characterization of a major colon cancer susceptibility locus (Ccs3) on mouse chromosome 3. Meunier C, et al. Oncogene volume 29, pages647–661 (2010).
Renal tumour suppressor function of the Birt-Hogg-Dubé syndrome gene product folliculin.
Hudon V, Sabourin S, Dydensborg AB, Kottis V, Ghazi A, Paquet M, Crosby K, Pomerleau V, Uetani N, Pause A. J Med Genet. 2010 Mar;47(3):182-9. doi: 10.1136/jmg.2009.072009. Epub 2009 Oct 19. PMID: 19843504
Partnerships
.jpg)
Discover our other
Research Areas
Rosalind & Morris Goodman Cancer Institute all rights reserved • Privacy policy • Accessibility
Website by Riposte
