Over the last 12 months, 101 scientific articles were published by our scientific community. 28% of those articles appear in very high-impact journals, which illustrates the excellence of our research.
Telomeres, structural caps at the ends of chromosomes, get shorter with each cell division. After sufficient erosion, their protective function is lost, activating the tumor suppressor gene p53 and the response to DNA damage. This leads to a non-proliferative state called senescence in normal cells, or cell death in cancer cells. Despite the importance of the mechanisms that trigger these processes, they are still poorly understood.
Lea Harrington's group, in collaboration with Mike Tyers and Pierre Thibault's groups at IRIC, recently performed human genome-wide screens to identify genes that enhance or inhibit the effects of telomere loss on proliferation of human cells in culture. They thus identified a gene encoding a protein of unknown function, which they named TAPR1 (for Telomerase Attrition and P53 Response 1). Their experiments showed that a role of TAPR1 is to buffer the deleterious effect on cells when p53 is activated by eroded telomeres and DNA damage.
Cells must optimize the p53 response to balance two opposing tendencies: Insufficient p53 activity allows the spread of damaged genomes that lead to tumorigenesis, while too much p53 activity can lead cells to premature senescence. TAPR1 represents a previously unknown genetic modulator of the delicate balance that governs p53 activity. Future research will determine whether modulation of TAPR1 activity could be used to promote cell viability in aging-related diseases or to sensitize cancer cells to cell death.
A novel p53 regulator, C16ORF72/TAPR1, buffers against telomerase inhibition
Benslimane Y, Sánchez‐Osuna M, Coulombe‐Huntington J, Bertomeu T, Henry D, Huard C, Bonneil É, Thibault P, Tyers M, Harrington L
A recent study by Michel Bouvier's group in collaboration with his colleagues at the Institut universitaire de cardiologie et de pneumologie de Québec, affiliated with Laval University, could pave the way for the treatment of early familial morbid obesity. People with this rare disease do not experience satiety, the message sent to our brain to stop hunger. As a result, they eat far too much, which leads to obesity and many complications, including very often type 2 diabetes.
Morbid obesity is caused in many cases by a mutation in the melanocotin receptor (the MC4R receptor) that prevents this receptor from being present on the surface of hypothalamus cells. In its absence, the action of melanocortin, a hormone that normally regulates appetite and energy expenditure, is prevented leading to obesity. Prof. Bouvier's team had previously discovered molecules called “pharmacological chaperones” that allow the defective receptor to be exported to the surface of cells and restore the action of melanocortin.
In this new study, the researchers describe a novel animal model, i.e. mice whose MC4R gene has been replaced by the normal or mutated human MC4R gene, and demonstrate that a pharmacological chaperone restores the function of the mutated MCR4 gene, and significantly reduced food intake in mice. Although we are still far from a pharmaceutical application in humans, these preclinical in vivo trials are very promising.
Pharmacological chaperone action in humanized mouse models of MC4R-linked obesity
René P, Lanfray D, Richard D, Bouvier M
The UM171 molecule was identified for its ability to amplify human cord blood stem cells in culture and is now in clinical development with more than 60 patients successfully transplanted after a 7-day ex-vivo expansion. Guy Sauvageau’s team, in collaboration with Anne Marinier, Mike Tyers and Pierre Thibault, has discovered one of the mechanisms of action of the molecule.
Using CRISPR-based screening and proteomic approaches, the teams identified the CULLIN3-E3 complex. Under the action of the UM171 molecule, the complex is able to target LSD1 corepressor complexes and cause their degradation via the proteasome. This restores several epigenetic marks, such as H3K4me2 and H3K27ac, which are physiologically diminished in ex-vivo cultures of hematopoietic stem cells. The discovery of this complex provides a better understanding of the process of cell expansion and self-renewal.
Chagraoui J, Girard S, Spinella JF, Simon L, Bonneil E, Mayotte N, MacRae T, Coulombe-Huntington J, Bertomeu T, Moison C, Tomellini E, Thibault P, Tyers M, Marinier A, Sauvageau G
Cytokines, which are chemical messengers, of the interleukin-17 (IL-17) family are involved in the body's defense against infections, but also in the development of chronic inflammatory disorders. One of the IL-17 binding receptors, interleukin-17 receptor D (IL-17RD), is known to downregulate signaling pathways that activate cell proliferation. Sylvain Meloche's team explored the anti-tumor functions of IL-17RD in a new study conducted in mice.
Using mouse models, the team first demonstrated that IL-17RD acted as a tumor suppressor in vivo. Disruption of the gene encoding IL-17RD indeed enhances tumor formation. Furthermore, for the model of colon cancer studied, the development of these tumors is associated with an exacerbated inflammatory response. The study shows IL-17RD limits the extent and duration of inflammation in epithelial cells in the gut. Since the genetic inactivation of IL-17RD does not impact cell signaling pathways or proliferation, the team concludes that the receptor’s antitumor action is due to this downregulation of inflammation.
Loss of interleukin-17 receptor D promotes chronic inflammation-associated tumorigenesis
Girondel C, Lévesque K, Langlois MJ, Pasquin S, Saba-El-Leil MK, Rivard N, Friesel R, Servant MJ, Gauchat JF, Lesage S, Meloche S
T lymphocytes are the master regulators of the immune response and understanding the regulation of their activity is a crucial issue in immunology as well as in the development of immunotherapies against cancer. A recent study by Etienne Gagnon's team sheds light on the cascade of events leading to robust T cell activation.
When pathogenic organisms enter the host's interior, specialized cells present antigens of these "intruders" to T cells. These are activated when the T cell receptor (called TCR) recognizes these antigens. The TCR is in fact a complex of 8 proteins, including the CD3 components which ensure the signaling of the TCR. At rest, the TCR remains dormant due to tight interactions between CD3 domains, which contain positive charges, and the plasma membrane of the cell whose inner leaflet is rich in lipids with a negative charge - mainly phosphatidylserine. When the TCR recognizes an antigen, it forms aggregates that exclude phosphatidylserine and this allows CD3 chains to dissociate from the membrane to initiate signaling. The IRIC researchers have demonstrated the role of the enzyme TMEM16F, which helps to redistribute the phosphatidylserine molecules to the outer layer of the plasma membrane, thereby increasing the dissociation of the CD3 domains from the plasma membrane and amplifying TCR signaling and the T lymphocytes response.
Connolly A, Panes R, Tual M, Lafortune R, Bellemare-Pelletier A, Gagnon E
Brian Wilhelm's team provides new insights into the understanding of acute myeloid leukemia (AML) induced by a chromosomal translocation involving the KMT2A gene. Molecular mechanisms of this disease were previously poorly defined. The group focused on the epigenetic mechanisms that can be disrupted in a leukemic context.
A murine model has been used to elucidate the initiating events of AML by characterizing all epigenetic mechanisms from initiation to the final development of the disease. This analysis provided an epigenetic picture that may be responsible for the dysregulation of genes in AML. In addition to identifying changes in DNA methylation and the distribution of histone marks, the laboratory identified genes that are potentially involved in leukemic development (ADCY9, CCL23). Chromatin analysis revealed that there were relatively few leukemia-specific changes and that the vast majority corresponded to regions of open chromatin and transcription factor clusters previously observed in other blood cell types. This study provides access to a mapping of epigenetic events at different stages of disease development.
Epigenetic changes in human model KMT2A leukemias highlight early events during leukemogenesis.
Milan T, Celton M, Lagacé K, Roques E, Safa-Tahar-Henni S, Bresson E, Bergeron A, Hebert J, Meshinchi S, Cellot S, Barabé F, Wilhelm B
During meiotic (production of genetically distinct cells) and mitotic (production of genetically identical cells) cell divisions, chromosomes are segregated towards the two poles of the cell. This segregation is triggered by the Anaphase-Promoting Complex, or Cyclosome, (APC/C), a huge protein complex that coordinates the degradation of targeted proteins. To accomplish its functions and allow sister chromatids separation, the APC/C must be phosphorylated at key sites. The work carried out by Vincent Archambault's team has identified cyclin B3 in the regulation of this process.
Cyclin B3 is required for the successful completion of anaphase, the stage of cell division during which chromosomes are segregated, during meiosis in many organisms. Using Drosophila, the team showed through genetic approaches that Cyclin B3 promotes anaphase during meiosis, but also during mitosis. In addition, Cyclin B3 promotes the activity of the APC/C in the cells studied. The team's results also show that Cyclin B3 associates with the APC/C, is required for the phosphorylation of one of its sites and promotes its association with its co-activators. The team concludes that Cyclin B3 directly activates the APC/C to promote anaphase during meiosis and mitosis.
Cyclin B3 activates the Anaphase-Promoting Complex/Cyclosome in meiosis and mitosis.
Garrido D, Bourouh M, Bonneil E, Thibault P, Swan A, Archambault V
Cell morphogenesis is the process by which cells adapt their structure to perform their different functions. The cytoskeleton, which acts as the scaffolding structure of the cell, plays key roles during this process. A new study by Sébastien Carréno's team dissects the functions of STRIPAK in a cascade of events regulating cell morphogenesis via the cytoskeleton.
Cytoskeletal proteins are anchored to the plasma membrane by, among others, the ERM family of proteins. ERM proteins alternate between cytosol inactive forms and plasma membrane active forms, the latter binding to the cytoskeleton. They are activated in a 2-step manner: the dissociation of their two domains, followed by their phosphorylation by the Slik kinase. The Carréno laboratory team discovered using Drosophila that the STRIPAK complex associates with the Slik kinase to promote its localization at the plasma membrane. The presence of Slik at the plasma membrane causes phosphorylation, and therefore activation, of its target, the dMoesin protein (the only member of ERMs in flies). The IRIC team has thus demonstrated a new role for the STRIPAK complex, via the regulation of Slik and dMoesin functions, in the control of cortical stability during mitosis and in the maintenance of epithelial integrity in the organism.
STRIPAK regulates Slik localization to control mitotic morphogenesis and epithelial integrity.
De Jamblinne CV, Decelle B, Dehghani M, Joseph M, Sriskandarajah N, Leguay K, Rambaud B, Lemieux S, Roux PP, Hipfner DR, Carréno S
Katherine Borden’s laboratory, with its collaborators from the United-States and Scotland, recently discovered that the activity of RNAs can be regulated in a new way: by modulating an RNA modification known as capping. The researchers discovered that eIF4E, a protein involved in cancer, unexpectedly modulates the capping of RNAs.
If one of the main functions of a gene is to encode the information necessary to synthesize a specific protein, it first needs to be copied into a so-called “messenger” RNA, which can itself undergo various modifications. One such modification is the addition of a cap, consisting of a methylated guanosine group, to the tip of the messenger RNA. The cap is important for the stability of coding RNAs and for the efficient synthesis of proteins from the messenger RNA. Capping was thought to be a housekeeping activity, in other words a constitutive modification.
Thanks to the development of new methods to quantify the amount of cap added to RNAs, the team showed that this is not the case, with many RNAs only 30-50% capped. Capping is instead a regulatable feature and thus provides a novel control mechanism for the cells. As eIF4E is involved in the development of malignant tumours, the authors also showed for the first time that capping of specific RNAs was highly elevated in primary cancer specimens and contributed to eIF4E’s oncogenic activity.
Culjkovic-Kraljacic B, Skrabanek L, Revuelta MV, Gasiorek J, Cowling VH, Cerchietti L, Borden K
Numerous small GTPase proteins in human cells work as switches to control whether intracellular signaling pathways are turned on or off. Of particular interest are GTPases of the RAS family since mutations in these GTPases are among the main causes of human cancers. “Effector” proteins, which specifically recognize and complex with activated GTPases act together with them to relay signals downstream. These effector proteins are attractive therapeutic targets, and a better understanding of their functions could have a broad impact.
The group of Professor Matthew Smith at IRIC, and their collaborators at the Hebrew University of Jerusalem, undertook a systematic analysis of the poorly studied members of the RAS-association domain family (RASSF) effectors. To their surprise, they found that only one of ten family members, RASSF5, binds activated RAS. Another surprise was that RASSF1-6 associate with the Hippo kinase and the other RASSFs interact with regulators of p53, an important tumor suppressor. They then used a structure and sequence-based informatics approach to identify GTPase partners of the protein RASSF1.
Importantly, interplay between RASSF1 and these new GTPases partners activated the Hippo pathway implicated in programmed cell death or apoptosis. As Hippo signaling is an emergent characteristic of RAS-driven cancers and their resistance to therapies, this systematic analysis of RASSF binding partners is an important first step in defining the molecular mechanisms involved.
RASSF effectors couple diverse RAS subfamily GTPases to the Hippo pathway
Dhanaraman T, Singh S, Killoran RC, Singh A, Xu X, Shifman JM, Smith M
A study led by the team of Philippe Roux, in collaboration with the teams of Louis Gaboury and Sylvain Meloche of IRIC, revealed that the oncogenic protein KRAS could be targeted indirectly. The KRAS oncogene is a protein involved in intracellular signaling and the response of cells to their environment. For three decades, scientists around the world have been trying to target this protein, which is frequently mutated in colorectal cancers. However, targeting in a direct and effective way the mutated forms of KRAS has revealed unsuccessful. Having developed an advanced proteomics technique to characterize cell-surface proteins, the IRIC scientists showed that mutation of this oncogene modifies the expression of proteins at the surface of the cells that cover the internal villi of the intestine.
With the collaboration of colleagues from the University of Toronto, McGill University and the United-States, they were able to identify the cell-surface protein ATP7A, a protein that transports copper, as an important molecule in the biology of colorectal cancers with a KRAS mutation. In addition, they highlighted that colorectal tumors contain more intracellular copper when KRAS is mutated and found that copper plays a major role in tumor progression, using mouse models of colorectal cancer.
This study therefore proposes two new therapeutic options for colorectal cancers carrying a KRAS mutation, that is targeted therapy against the ATP7A protein or blocking the action of intracellular copper using therapeutic approaches that already exist.
Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer
Aubert L, Nandagopal N, Steinhart Z, Lavoie G, Nourreddine S, Berman J, Saba-El-Leil MK, Papadopoli D, Lin S, Hart T, Macleod G, Topisirovic I, Gaboury L, Fahrni CJ, Schramek D, Meloche S, Angers S, Roux PP
The team of Philippe Roux, in collaboration with the teams of Sébastien Carréno and Michel Bouvier from IRIC, have recently discovered a new mechanism for the regulation of the cell cycle. This life cycle of the cell is a complex process separated into several key steps, the final one being mitosis. Different “quality control” mechanisms operate at each of the key steps and may or may not allow the cycle to continue on its course.
The IRIC researchers have identified the RNA binding proteins NF45 and NF90 as major regulators of the cell cycle. These proteins are indeed essential for the expression of a group of genes, themselves necessary for the progression of mitosis. Their study revealed that this regulation takes place at the mRNA level of these genes, through competition between the proteins NF45 and NF90, and another RNA binding protein, Stau2. The latter is responsible for the degradation of mRNAs that do not meet the "quality control" standards. If NF45 and NF90 manage to bind to mRNAs in place of Stau2, the mRNAs are stabilized and the cell cycle can progress to mitosis.
This work provides a potential explanation for the observed overexpression of the NF45-NF90 complex in cancer cells, which could be responsible for the aberrant proliferation of these cells. This study suggests that these proteins could be new therapeutic targets against different types of cancer.
NF45 and NF90 Regulate Mitotic Gene Expression by Competing with Staufen-Mediated mRNA Decay
Nourreddine S, Lavoie G, Paradis J, Ben El Kadhi K, Méant A, Aubert L, Grondin B, Gendron P, Chabot B, Bouvier M, Carréno S, Roux PP
The group led by Lea Harrington, with its collaborators from Toronto, recently identified a molecular mechanism linking telomeres and epigenetic regulation in stem cells.
Telomeres are particular DNA sequences at the end of chromosomes that serve as caps to protect against degradation. They are maintained by an enzyme called TERT and are essential to maintain genome integrity and cell viability. Telomere dysfunction is also known to impair stem cell differentiation but the mechanism involved was unknown.
The researchers focused on stem cells genetically modified to be TERT deficient (Tert-/-) and that display significantly shortened telomeres. They first demonstrated that cells were unable to become fully differentiated or to maintain the differentiated state. These cells continued to express genes typical of stem cells rather than differentiated cells. They then showed that Tert-/- cells displayed a global alteration in the accessibility of DNA and in gene regulation, and that these anomalies were accompanied by changes in a particular epigenetic modification, the “H3K27me3 repression mark”. This epigenetic mark is known to inactivate the genes that would otherwise maintain cells in a stem cell-like, undifferentiated state.
The identification of such a functional link between telomere erosion and disruption in epigenetic regulation of gene expression, could lead to new opportunities in the treatment of age-associated diseases including cancers.
Criqui M, Qamra A, Chu TW, Sharma M, Tsao J, Henry DA, Barsyte-Lovejoy D, Arrowsmith CH, Winegarden N, Lupien M, Harrington L.