https://rottapellab.com/team daily 0.75 2023-05-30 https://images.squarespace-cdn.com/content/v1/60e35206e551c56264f2b5e6/1625759323190-3DGKOPH3MGX2NMUIWOH6/lab+photo.png Team https://images.squarespace-cdn.com/content/v1/60e35206e551c56264f2b5e6/1631898260744-3CFN375TTL3K4B5BNCRX/rottapel.jpg Team - PRINCIPAL INVESTIGATOR Dr. Robert Rottapel Dr. Rottapel is a Senior Scientist at the Princess Margaret Cancer Centre where he holds the Amgen Chair for Cancer Research. He is a Professor in the Departments of Medicine, Immunology and Medical Biophysics at the University of Toronto. After completing his medical studies at George Washington University, the NIH and UCLA, he pursued his postdoctoral studies with Allan Bernstein at the Lunenfeld Research Institute in Toronto and with Patrice Dubreuil at INSERM, France. Dr. Rottapel is a clinical rheumatologist at St. Michael's Hospital, University of Toronto. His clinical expertise is in monogenic autoinflammatory disorders and the autoimmune adverse effect resulting from checkpoint inhibitors in cancer patients. https://images.squarespace-cdn.com/content/v1/60e35206e551c56264f2b5e6/471a55ed-1331-4750-b1c9-ffbee573f5fb/IMG_2040_R.jpg Team - POST-DOCTORAL FELLOW Dr. Yosuke Asano Dr. Yosuke Asano received his Ph.D. from the department of Nephrology, Rheumatology, Endocrinology and Metabolism at Okayama University, Japan, in 2023. During his doctoral thesis, he studied the efficiency of endonuclease for osteoblast collection, and also studied the relationship between pharmacologic inhibition of tankyrase and inflammatory cytokine production. In the Rottapel lab, his work is focused on the relationship between adaptor protein 3BP2 and osteoblasts. Previous members in the Rottapel lab have reported the effects of 3BP2 in osteoblasts. He will aim to clarify how 3BP2 contributes to proliferation, differenciation and survival of osteoblasts. https://images.squarespace-cdn.com/content/v1/60e35206e551c56264f2b5e6/1625838186735-A2M3UK8H3P7AJ0N0CVUH/Donna+photo.jpg Team - ADMINISTRATIVE ASSISTANT Donna DeFrancesco Since 1995, Donna De Francesco has provided professional administrative assistance to many clinical and research offices at the University Health Network. Donna has worked on many special projects throughout her career including the NCIC Program Project Grant; the cost recovery project at the Hospital for Sick Children Research Institute; Princess Margaret Hospital Foundation Myeloma Fund; organization of FASEB meetings and coordinating the Terry Fox Ontario Node Symposium for a number of years. Through UHN, Donna also worked for two years on a special contract with Senior Scientist Mike Moran at The Hospital for Sick Children. Donna continues to provide professional administrative services to clinician/senior scientist Robert Rottapel, and to a new clinician/scientist at UHN and PMCRT, Dr. Phedias Diamandis, Neuropathologist. Donna is the primary contact for their offices and laboratories at the University Health Network. https://images.squarespace-cdn.com/content/v1/60e35206e551c56264f2b5e6/1625838458110-Q4HMCI6NPJ2WU3CY7GO7/Tian+photo.png Team - POST-DOCTORAL FELLOW Dr. Tian Sun Dr. Tian Sun received her Ph.D. from the Department of Immunology at the University of Toronto in 2017. Her Ph.D. work focused on the investigation of antiviral adaptive immune responses in the gut. Specifically, her work illustrated the subtypes of dendritic cells that are important in mounting antigen-specific T cell responses. She also identified non-redundant roles of the lymphotoxin beta receptor signaling pathway and NLRC5 in mucosal immunity. Previous members in the Rottapel lab have identified that the autocrine loop of relaxin signaling is essential for proliferation and tumourigenesis of high-grade serous ovarian cancer cells. Tian is carrying the relaxin story forwar to develop relaxin neutralizing antibodies as a therapeutic agent to treat high-grade serous ovarian cancers in the Rottapel lab. https://images.squarespace-cdn.com/content/v1/60e35206e551c56264f2b5e6/1625860348396-9DTNCH521JS7KHU01QAD/Justin-Cowen.jpeg Team - DOCTORAL STUDENT Justin Cowen Justin received his Bachelor of Science (Honours) degree in Biochemistry from Queen’s University. His undergraduate research with Dr. Peter Greer focused on the control of actin branching by the Arp2/3 complex in triple-negative breast cancer. As a PhD candidate in the Department of Medical Biophysics at the University of Toronto, his research focuses on the role of GEF-H1 in pancreatic cancer. Justin is currently studying cell signaling pathways that link GEF-H1 and cytoskeletal architecture to the Hippo pathway, in collaboration with Dr. Boris Hinz at the Faculty of Dentistry. His work looks at how these pathways may contribute to cancer growth, invasion, and maintenance of the tumour microenvironment. https://images.squarespace-cdn.com/content/v1/60e35206e551c56264f2b5e6/1625759523325-06QR8K6NEFQMFGYOR8V0/josecol.jpg Team - LAB MANAGER Jose La Rose Jose La Rose has been the lab manager for Dr. Rottapel for approximately 24 years. His background is molecular biology at the University of Toronto. The Rottapel lab acquires data using a wide range of techniques so his experience has grown beyond that of molelcular biology. He started with a passion for benchwork and this remains the same to this day. https://images.squarespace-cdn.com/content/v1/60e35206e551c56264f2b5e6/1625759563402-8D5U50JKT1M9YXEYOJUE/kylecol.jpg Team - POST-DOCTORAL FELLOW Dr. Kyle Francis Dr. Kyle Francis received his PhD in Molecular and Clinical Medicine (Pathology) from the University of Edinburgh. His doctoral thesis involved studying checkpoint kinases as druggable targets in ovarian cancer. He joined the lab to identify new therapeutic vulnerabilities in high-grade serous ovarian cancer (HGSOC) using functional genomics. Dr. Francis’ work involves studying the regulation of immunogenic RNA by nonsense mediated decay (NMD) in HGSOC. His research has identified a therapeutic window where NMD inhibition induces cell death and presents a unique set of MHC class I-associated antigens for tumour immune detection. Ongoing work involves studying the immune-mediated effects of NMD inhibition on HGSOC progression. https://images.squarespace-cdn.com/content/v1/60e35206e551c56264f2b5e6/c2472b8b-254c-4bb0-8a9f-c8aa8342b690/unnamed.jpg Team - DOCTORAL STUDENT Munira Verdawala Munira Verdawala received her B.Sc. (honors) from Ryerson University in Biomedical Sciences with a minor in Physics. At Ryerson, Munira worked under the supervision of Dr. Roberto Botelho to uncover and investigate the molecular mechanisms that limit phagocytic appetite. Munira joined the Department of Immunology at the University of Toronto as a member of the Rottapel Lab in August 2021 to pursue her PhD. Munira is currently studying the role of the adaptor protein 3BP2 and its inhibitor Tankyrase in macrophages. Specifically, her work aims to elucidate underlying signaling pathways. In addition, Munira is also working with Ryder to evaluate the effects of mutations in the Rho-GTPase Cdc42 in macrophages. https://images.squarespace-cdn.com/content/v1/60e35206e551c56264f2b5e6/e6de04d9-d997-4d86-9c2e-6b91a80a26bf/image0.jpg Team - POST-DOCTORAL FELLOW Dr. Oro Uchenunu Dr. Oro Uchenunu completed his PhD in Experimental Medicine from McGill University at the Lady Davis Institute in Montreal under the supervision of Drs. Ivan Topisirovic and Michael Pollak. His doctoral thesis involved investigating perturbations in energy metabolism to identify targetable metabolic vulnerabilities in cancer. His work elucidates plausible adaptive mechanisms that cancer cells turn on to survive energetic stress due to nutrient deprivation or inhibition of mitochondrial complexes. His work provides previously unrecognized insights into metabolic adaptation and plasticity of cancer cells. Dr. Uchenunu joined Dr. Rottapel’s lab in 2023 as a postdoctoral researcher to elucidate the role of GCN2 in High-Grade Serous Ovarian Cancer (HGSOC) under nutritional and chemotherapeutic stress. His current research involves the use of novel small molecule GCN2 inhibitors in combination therapies to better understand the mechanistic functions of GCN2. This may open new avenues to treat HGSOC. https://images.squarespace-cdn.com/content/v1/60e35206e551c56264f2b5e6/736b0db4-a631-484f-84c2-e4aa33ef6c31/Picture.jpg Team - POST-DOCTORAL FELLOW Dr. Pallavi Mathur Dr. Pallavi Mathur received her PhD in Cell and Development Biology from Institut Curie, Paris, France, in 2022. During her doctoral thesis, she studied the changes in organelle organization that accompany tumorigenesis. Using normalized cell cultures on adhesive micropatterns in a bladder cancer model, it was observed that lysosomal positioning becomes increasingly scattered towards the cell periphery in aggressive bladder cancer cells. Mechanistically, her work has shown that lysosome positioning is under the control of Transcription factor EB (TFEB) and that hyperactivation of TFEB leads to the characteristic cellular phenotype of lysosome dispersion in aggressive bladder cancer cells. Moreover, activation of TFEB leads to a global increase of phosphatidylinositol-3-phosphate (PI3P) at lysosomes and strong recruitment of FYVE-domain-containing proteins, thus uncovering a novel role of TFEB in regulating cellular PI3P levels. In Rottapel lab, her work is focused on studying kinases important for formation and metastasis of high-grade serous ovarian cancer (HGSOC) spheroids. These multicellular spheroids are found in malignant ascites that accompanies peritoneal dissemination of ovarian cancer. Additionally, Pallavi is also studying the role of Akt signaling pathway in regulation of nonsense-mediated decay (NMD) in HGSOC. https://rottapellab.com/contact daily 0.75 2021-07-09 https://images.squarespace-cdn.com/content/v1/60e35206e551c56264f2b5e6/1625592264606-H2C0N8TCOUZNS7NLOUGC/MaRS-Discovery-Tower_V-1000x1618.jpg Contact - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://rottapellab.com/research daily 1.0 2023-07-12 https://images.squarespace-cdn.com/content/v1/60e35206e551c56264f2b5e6/1632248473436-TFTX07JT4FTN4SZKIGSK/triple-ROI.png Rottal Lab - Emergent Vulnerabilities in Ovarian Cancer As cancer cells evolve, they acquire new fitness properties through genetic mutation that ensures their survival and proliferative potential. However, the acquisition of new fitness properties is often associated with the acquisition of genomic, proteotoxic, metabolic, immunoreactive and oxidative stress, stress states that must be mitigated for the cancer cells to survive. We are systematically identifying the emergent adaptation pathways required for ovarian cancer cell survival using functional shRNA and CRISPR synthetic lethal screens. We have recently identified an essential autocrine loop involving the secreted protein Relaxin and its receptor RXFP1 in ovarian cancer. We are currently developing neutralizing monoclonal antibodies targeting Relaxin and testing their therapeutic potential. We have identified the tetraspanin CD151 as an essential gene in HGSOC. CD151 is required for the activation of the SRC and FAK pathways in ovarian cancer cell lines of mesenchymal phenotype; is expressed in a high percentage of primary ovarian cancer tumors; and is biomarker of poor clinical outcome. https://images.squarespace-cdn.com/content/v1/60e35206e551c56264f2b5e6/3bae4b94-351b-4324-ab4a-c8136a7bbed6/KI+macrophage+SEM.jpg Rottal Lab - Metabolic Targeting of Solid Tumours We have identified several integrated stress kinases including the amino acid sensor GCN2 as potential therapeutic targets for ovarian cancer and other tumor types. The therapeutic potential of these targets is currently being developed. We discovered that ovarian cancer cells are highly dependent on the mRNA quality control nonsense mediated decay (NMD) pathway. We have shown that NMD regulates the immuopeptidome on ovarian cancer cells suggesting that inhibition of NMD may be a way to enhance the immunogenicity of tumor cells. We are using genetic and pharmacologic approaches to uncover the mechanistic basis of these emergent essential signaling pathways. https://images.squarespace-cdn.com/content/v1/60e35206e551c56264f2b5e6/1631899975091-27E9KQEDD2UJ1VCH65Q1/Composite.png Rottal Lab - Regulation of the Rho guanine nucleotide exchange factor GEF-H1 We have discovered that the RHOA guanine nucleotide exchange factor GEF-H1 is sequestered in an inhibited state on microtubules by the dynein motor complex. GEF-H1 release and activation is critically important for the formation of actin contractile structures and the coordinated activation of the MAPK and YAP signaling pathways. These observations demonstrate that cell signaling is critically contingent on the state of cytoskeleton elements a point of control that can be lost in cancer cells. https://images.squarespace-cdn.com/content/v1/60e35206e551c56264f2b5e6/1645318420377-AQD1O7J8QEF73U7QH6SQ/Screen%2BShot%2B2022-02-19%2Bat%2B3.52.17%2BPM.jpg Rottal Lab - Modeling Genetic Autoinflammatory Syndromes We have studied Cherubism, a dominantly inherited disorder leading to facial dysmorphia and activation of immune cells. Mutations in the adapter protein 3BP2 mutated in Cherubism patients leads to hyperactivation of Src, Abl, Syk tyrosine kinases and the guanine nucleotide exchange factor Vav. 3BP2 protein levels are negatively regulated by Tankyrase and the ubiquitin ligase RNF146. Our knockout studies have shown that 3BP2 is required for the activation of T cells, B cells, and neutrophils. We have recently shown loss of 3BP2 control leads to inflammatory bowel syndrome, macrophage activation, inflammatory cytokine production because of Toll like receptor 2 hyperactivation. We are currently studying the role of 3BP2 in macrophage function, phagocytosis and the uptake of oxidized lipid particles by scavenger receptors such as CD36. We are currently studying the mechanism underlying a recently described autoinflammatory syndrome characterized by neonatal onset of pancytopenia, autoinflammation, rash, and hemophagocytic lymphohistiocytosis called NOCARH. This disorder has mutations in the C-terminus of CDC42. https://images.squarespace-cdn.com/content/v1/60e35206e551c56264f2b5e6/622ab673-63d8-40a3-9f9b-0b0cf7ac88ea/m_jimmunol_208_12_cover.png Rottal Lab Translational Control by 4E-BP1/2 Suppressor Proteins Regulates Mitochondrial Biosynthesis and Function during CD8+ T Cell Proliferation https://images.squarespace-cdn.com/content/v1/60e35206e551c56264f2b5e6/a274d5b5-9ce6-4ff0-9d7f-ed99244514f5/132-7-cover.jpg Rottal Lab Tankyrase represses autoinflammation through the attenuation of TLR2 signaling https://images.squarespace-cdn.com/content/v1/60e35206e551c56264f2b5e6/1625513774345-GA0JUCRKMD8I35SWX9V6/m_jcb_220_7.cover.png Rottal Lab Tankyrase regulates epithelial lumen formation via suppression of Rab11 GEFs https://images.squarespace-cdn.com/content/v1/60e35206e551c56264f2b5e6/1625513824780-8E5PG3QPH6YRCMM6UVMS/131-7-cover.jpg Rottal Lab Inhibition of relaxin autocrine signaling confers therapeutic vulnerability in ovarian cancer https://rottapellab.com/publications daily 0.75 2023-05-12 https://images.squarespace-cdn.com/content/v1/5ec321c2af33de48734cc929/1607694644871-IC85FNH781UNZSZEGHDR/Aro+Ha_0428.jpg Publications https://images.squarespace-cdn.com/content/v1/5ec321c2af33de48734cc929/1618497259178-6XJGK9GR6YAVBQL5L519/20140301_Trade-151_012-2.jpg Publications https://images.squarespace-cdn.com/content/v1/5ec321c2af33de48734cc929/1607694583486-2PQT0LQ193RL7MCB6DX4/20140228_Trade+151_0046.jpg Publications https://rottapellab.com/news daily 0.75 2021-10-04