LMP student seminars: 16 December
Each week during term time, MSc and PhD candidates in the Department of Laboratory Medicine and Pathobiology present their research.
Anyone is welcome. No need to register.
Location: Medical Sciences Building, rooms 4171 or 4279, see below.
As part of the core research curriculum, students taking LMP1001/2/3: Graduate Seminars in Laboratory Medicine and Pathobiology will present their projects. Please see abstracts below.
2. Cancer, Development and Aging
Location: MSB 4171
Lydia Leung
- Title: Evaluating the Efficacy of the SickKids’ Radiation-Sparing Regimen for Treatment of Atypical Teratoid Rhabdoid Tumor
- Supervisor: Dr. Annie Huang
Andrew Yim
- Title: Delineating the Molecular Mechanisms Underlying Lineage Transdifferentiation in Established Cancers
- Supervisor: Dr. Rod Bremner
1. Brain and Neuroscience
Location: MSB 4279
Thomas Zerbes
- Title: Adeno-associated viruse (AAVs) for the treatment of prion disease
- Supervisor: Dr. Gerold Schmitt-Ulms
He Huang
- Title: The Dynamics of Neural Stem Cells in Brain Injuries
- Supervisor: Dr. Scott Yuzwa
Abstracts
Lydia Leung: Evaluating the Efficacy of the SickKids’ Radiation-Sparing Regimen for Treatment of Atypical Teratoid Rhabdoid Tumor
Atypical teratoid rhabdoid tumors (ATRT) are rare and highly aggressive pediatric brain tumors, characterized by bi-allelic SMARCB1 gene loss. Treatment comprises a multimodal approach including surgery, chemotherapy, and craniospinal radiation, which cure only a small proportion of patients. Irradiation has been linked to severe neurocognitive consequences, leading to reluctance in using radiation to treat young patients. Moreover, disease remission following consolidation does not indicate sustained disease response, highlighting the need for further therapy to treat microscopic disease. To address these gaps, SickKids developed an innovative standard-of-care (SKSOC) regimen that aims to avoid or delay radiation by using intrathecal chemotherapy (IT) administered directly into the cerebrospinal fluid to prevent or treat metastatic craniospinal disease. Additionally, it incorporates an extended maintenance phase to target residual microscopic disease. However, it is not known whether this regimen improves outcomes. I hypothesize that the use of IT and additional maintenance therapy improves survival in ATRT patients. I identified 27 ATRT patients treated on the SKSOC between 2005-2024 and survival analysis demonstrates a 4-yr EFS of 43% and OS of 61%. Univariate analysis showed metastatic disease and incomplete tumor resection are significant negative risk factors for both EFS and OS. To further assess the efficacy of the SKSOC, I will compare the SKSOC data with the prospective ACNS0333 clinical trial and larger ATRT cohort in the Rare Brain Tumor Consortium to evaluate whether the SKSOC regimen impacts outcomes. Findings from my project will help tailor ATRT therapy and reduce excessive treatment and toxicity in young patients.
Andrew Yim: Delineating the Molecular Mechanisms Underlying Lineage Transdifferentiation in Established Cancers
Despite the daunting complexity of cancer, our lab found that all tumours fit into just two classes with distinct vulnerabilities based on the expression or absence of the transcriptional coactivator YAP and its paralog TAZ (WWTR1). YAPon cancers, which include most solid cancers, deploy YAP/TAZ to drive division, a pro-cancer activity. In contrast, YAPoff cancers, including all blood and neuroendocrine (NE) cancers as well as many neural tumors, epigenetically silence YAP/TAZ and extracellular matrix (ECM) and adhesion YAP/TAZ target genes which otherwise would cause cytostasis. Tumours can shift cell identity to evade therapeutics. Of note, YAPon lung adenocarcinoma (LUAD) transdifferentiates into lethal YAPoff NE small cell lung cancer (SCLC). This shift is linked to loss of the tumour suppressors RB1 and TP53, and activation of the transcription factor ASCL1. Critically, YAP/TAZ are silenced, which is logical as forced YAP/TAZ expression causes cytostasis in SCLC. Currently, there are no in vitro models to dissect this lethal lineage switch. Manipulation of key nodes, including RB, ASCL1 and YAP/TAZ, will be essential to building the first LUAD to SCLC model. We have found that deleting RB1 in TP53 null lung adenocarcinoma cell lines and activating a doxycycline inducible ASCL1 vector promotes the NE lineage in a limited subset of LUAD cell populations, suggesting a molecular program inhibiting dominant transdifferentiation to SCLC. To overcome this repression, we successfully synthesized cell lines expressing a custom designed self-selecting Synergistic Activation Mediator (SAM) CRISPR-activation vector. This compact system enables the selective upregulation of key neuroendocrine drivers, including ASCL1, ONECUT2, and INSM1. Our TradeSeq analysis corroborates these markers by discerning three distinct populations of LUAD, semi-LUAD/SCLC, and SCLC in cell lines and in vivo, suggesting the existence of an intermediary state harboring these drivers between the adenocarcinoma and small-cell lineages. If successful in vitro transdifferentiation is achieved, scRNAseq will be employed to distinguish the molecular landscape underlying classical SCLC from transdifferentiated SCLC to assess the extent of conversion to a single-cell resolution. Developing a LUAD-SCLC conversion model is vital for future functional genomics assays to reveal to uncover the entire network driving this lethal event. By generating the first in vitro model for LUAD-SCLC switching, my work may expose novel SCLC vulnerabilities. Treatment for this highly lethal cancer has barely changed in forty years, thus new therapeutic avenues are of major clinical interest.
Thomas Zerbes: Adeno-associated viruse (AAVs) for the treatment of prion disease
Prion diseases are rare, invariably fatal neurodegenerative disorders that affect both humans and animals. These diseases are caused by the accumulation of an abnormally folded form of the prion proteins, called Prp scrapie or PrpSc. It is the only known type of disease that manifests in three distinct ways – sporadic (spontaneous), familial (genetic), or infectious. The most commonly known prion disease is bovine spongiform encephalopathy (BSE) or “mad cow disease”. Creutzfeldt-Jakob disease (CJD) is the most prevalent human prion disease, characterized by rapid cognitive decline and motor dysfunction. It is associated with a lifetime risk of dying of around 1:5-10,000.
Current treatment strategies focus mostly on reducing the levels of the physiological PrpC. These include, among others, the CRISPR-based genome editing and antisense oligonucleotides (ASOs) to decrease the expression levels of the prion protein. One of the biggest challenges, however, remains the effective CNS delivery of these agents.
Adeno-associated viruses (AAVs) have emerged as promising delivery strategy for gene therapy due to their ability to efficiently transport therapeutics into the CNS. This presentation seeks to present various strategies for optimizing AAV-based delivery. This includes different preparation methods for AAVs (AAVX affinity capture or iodixanol gradient), the selection of improved AAV capsids for enhanced CNS targeting (AAV9, PHP.eB, and 9P31), the optimization of the payload plasmid, and the various routes of administration (intracerebral and retro-orbital sinus injection) in a combined effort to improve therapeutic delivery to the brain.
He Huang: The Dynamics of Neural Stem Cells in Brain Injuries
During the mammalian brain development, neural stem cells (NSCs) switch from a fast-proliferating state in the embryonic neocortex to a quiescent state in the adult. My research is to characterize the complex dynamics of NSCs in brain injuries. NSCs are mobilized to aid brain recovery after injuries. Also, brain injuries profoundly change the NSC lineage progression.
The transition of NSCs from quiescent to active state after brain injury is driven by extracellular signals. I used bioinformatic inference of spatial transcriptomic data to identify the intercellular signaling after ischemic stroke. I identified a potential negative regulatory protein of NSC proliferation and validated its function both in vitro and in vivo. I am further investigating the signaling pathway involved in this regulation mechanism.
Besides intercellular signaling, another aspect of the dynamics of NSCs after brain injuries is the impact of brain injuries on the fate mapping of NSCs. I used diffused white matter injury (dWMI) model to study the oligodendrocyte (OL) lineage progression during perinatal development. The pathogenesis of dWMI involves the initial loss of preOLs, followed by rapid proliferation of OL progenitor cells (OPCs) to replenish the preOL pool and astrogliosis. The formation of “glial scar” arrests the maturation of preOLs, causing the accumulation of the preOLs. The underpinning mechanism is unknown. Here I used spatial transcriptomics to characterize the gene expression profiles and identified several key genes in OL maturation. I am also exploring the intercellular signaling which accounts for the arrest of OL maturation by gliosis.
Taken together, my research may shed light on the complex process of NSC mobilization after brain injuries and how brain injuries reshape the NSC lineage progression.
Contact
No need to register.
Contact lmp.grad@utoronto.ca with any questions