A5069158861- Pancreatic and Hepatic Oncology Research
- Cancer Cells and Metastasis
- DNA Repair Mechanisms
- Cancer Genomics and Diagnostics
- Immune cells in cancer
- Epigenetics and DNA Methylation
- Single-cell and spatial transcriptomics
- PARP inhibition in cancer therapy
- RNA modifications and cancer
- BRCA gene mutations in cancer
- Cell Image Analysis Techniques
- Metabolism, Diabetes, and Cancer
- Platelet Disorders and Treatments
- Neuropeptides and Animal Physiology
- Protease and Inhibitor Mechanisms
- RNA and protein synthesis mechanisms
- Biochemical and Molecular Research
- Acute Myeloid Leukemia Research
- Cancer Immunotherapy and Biomarkers
- Pediatric Hepatobiliary Diseases and Treatments
- Liver physiology and pathology
- Genetic and Kidney Cyst Diseases
- Cancer, Hypoxia, and Metabolism
- Peptidase Inhibition and Analysis
- Data Visualization and Analytics
Princess Margaret Cancer Centre
2019-2025
University Health Network
2019-2025
Toronto Metropolitan University
2022
University of Toronto
2020
Intratumoral heterogeneity is a critical frontier in understanding how the tumor microenvironment (TME) propels malignant progression. Here, we deconvolute human pancreatic TME through large-scale integration of histology-guided regional multiOMICs with clinical data and patient-derived preclinical models. We discover "subTMEs," histologically definable tissue states anchored fibroblast plasticity, relationships to immunity, subtypes, differentiation, treatment response. "Reactive" subTMEs...
The cytosolic dipeptidyl-aminopeptidase 9 (DPP9) cleaves protein N-termini post-proline or -alanine. Our analysis of DPP9 mRNA expression from the TCGA 'breast cancer' data set revealed that low/intermediate levels are associated with poor overall survival breast cancer patients. To unravel impact on development and progression, transgenic MMTV-PyMT mouse model metastasizing was used. In addition, tissue- time-controlled genetic deletion by Cre-loxP recombination system done. Despite a delay...
Abstract Integration and mining of bioimaging data remains a challenge lags behind the rapidly expanding digital pathology field. We introduce Hourglass, an open‐access analytical framework that streamlines biology‐driven visualization, interrogation, statistical assessment multiparametric datasets. Cognizant tissue clinical heterogeneity, Hourglass systematically organizes observations across spatial global levels within patient subgroups. Applied to extensive dataset, promptly consolidated...
It is widely assumed that all normal somatic cells can equally perform homologous recombination (HR) and non-homologous end joining in the DNA damage response (DDR). Here, we show DDR mammary gland inherently depends on epithelial cell lineage identity. Bioinformatics, post-irradiation repair kinetics, clonogenic assays demonstrated luminal exhibiting a more pronounced HR compared to basal lineage. Consequently, progenitors were far sensitive poly(ADP-ribose) polymerase inhibitors (PARPis)...
ABSTRACT Cancer metabolism adapts the metabolic network of its tissue-of-origin. However, breast cancer is not a disease singular origin. Multiple epithelial populations serve as culprit cell-of-origin for specific subtypes, yet knowledge surrounding normal mammary cells limited. Here, we show that have cell type-specific programs. Primary human proteomes basal, luminal progenitor, and mature revealed their unique enrichment proteins. Luminal progenitors had higher abundance electron...
Abstract Pancreatic ductal adenocarcinoma (PDAC) has a complex disease pathobiology and poor treatment options, emphasizing the need for novel therapeutic targets. Hub genes have high connectivity (i.e., exceptionally many interaction partners), example, certain proteases with numerous partners. Thereby, hub are often central biological regulators dysregulated proteolysis is indeed key trait of malignant tissues. Here, we aimed to identify protease-related potential involvement in pancreatic...
ABSTRACT We describe the anatomy of replication forks by comparing lengths synthesized BrdU-labelled DNA in wild-type, mrc1Δ and cds1Δ Schizoasaccharomyces pombe . correlated Rad51 Cdc45 proteins relative to their positions on fork, replicated tract, or unreplicated regions. did this using chromatin spread pixel intensity data that was analyzed our program: R-ODD-BLOBS. Graphs BrdU proteins, as well percentage colocalization, were created program. These results compared literature. The...
Understanding cell fate regulation in the liver is necessary to advance therapies for hepatic disease. Liver progenitor cells (LPC) contribute tissue regeneration after severe injury yet signals instructing dynamics and are largely unknown. The Tissue Inhibitor of Metalloproteinases, TIMP1 TIMP3 control sheddases ADAM10 ADAM17, key NOTCH activation. Here we uncover role TIMP/ADAM/NOTCH/DLK1 axis LPC maintenance cholangiocyte specification. Combined TIMP1/TIMP3 loss vivo caused abnormal...
Bone marrow (BM) is the primary site of hematopoiesis and responsible for a lifelong supply all blood cell lineages. The process follows key intrinsic programs that also integrate instructive signals from BM niche. First identified as an erythropoietin-potentiating factor, tissue inhibitor metalloproteinase (TIMP) protein family has expanded to 4 members widely come be viewed classical regulator homeostasis. By virtue metalloprotease inhibition, TIMPs not only regulate extracellular matrix...
Abstract Pancreatic ductal adenocarcinoma (PDAC) displays a high degree of spatial subtype heterogeneity. This intratumoral co-existence classical and basal-like programs is evident in multi-scale transcriptomic analyses resected, advanced-stage chemotherapy-treated specimens reciprocally linked to diverse stromal immune microenvironment as well worse clinical outcome. However, the underlying mechanisms heterogeneity remain largely unclear. Here, by combining preclinical models, multi-center...
Summary Pancreatic ductal adenocarcinoma (PDAC) remains resistant to most treatments and demonstrates a complex pathobiology. Here, we deconvolute regional heterogeneity in the human PDAC tumor microenvironment (TME), long-standing obstacle, define precise stromal contributions progression. Large scale integration of histology-guided multiOMICs with clinical data sets functional vitro models uncovers two microenvironmental programs that were anchored fibroblast differentiation states. These...
Abstract It has long been assumed that all normal cells have the same capacity to engage homologous recombination (HR) and non-homologous end joining (NHEJ) repair DNA double-strand breaks (DSBs), a concept exploited for DNA-damaging chemotherapeutics. We show mammary epithelial lineage dictates DSB pathway choice. Primary proteomes enumeration by γ-H2AX, Rad51 DNA-PKc foci reveal NHEJ operates in cells, but high-fidelity HR is restricted luminal lineage. This translates divergent poly...
In biology, microscopy data from thousands of individual cellular events presents challenges for analysis and problem solving. These include a lack visual tools to complement algorithmic approaches tracking important but rare events, support collaborative exploration interpretation. response these challenges, we have designed implemented Tangible Chromatin, tangible multi-surface system that promotes novel complex generated high-content experiments. The facilitates three specific analysis:...
Abstract It has been nearly 3 decades since the discovery of BRCA1/2 genes and their link to breast cancer risk, with prophylactic mastectomy remaining primary management option for these high-risk mutation carriers. The current paucity interception strategies is due undefined, targetable precursor populations in breast. Despite known cellular alterations BRCA1 breast, epithelial at root unwarranted cell state transitions remain unresolved. Here, we identify a progenitor population that...
Abstract Pancreatic ductal adenocarcinoma (PDAC) remains mostly untreatable while its incidence is on the rise. PDAC stroma should be a reservoir for novel therapeutic targets. Yet, stromal cellular complexity and an extensive intratumoral heterogeneity in human patients have left functions of poorly understood likely hamper targeting. Here, we set out to deconvolute regional assess role disease progression. Using resected & advanced biospecimens with known patient outcome, mapped...
Summary Recent advances in digital pathology have led to an explosion high-content multidimensional imaging approaches. Yet, our ability gainfully process, visualize, integrate and mine the resulting mass of bioimaging data remains a challenge. We developed Hourglass, open access user-friendly software that streamlines complex biology-driven post-processing visualization multiparametric data. Directed at datasets derived from tissue microarrays or methods analyze multiple regions interest...
Abstract Effective treatments for Pancreatic ductal adenocarcinoma (PDAC) remain an urgent need. Integration of molecular PDAC subtypes into clinical trials could enable translational insights how we might refine existing and emerging therapies to improve treatment options, yet this requires robust clinically suitable marker genes a better understanding subtype-related biology. Here, deeply profiled the composition human epithelia assessed differentially expressed their ability discriminate...
Abstract Intratumoral heterogeneity is a critical frontier in understanding how the tumor microenvironment (TME) propels malignant progression. We recently deconvoluted regional human PDAC stroma to assess its role disease progression and discovered two types of ‘sub-tumor microenvironments’ (subTMEs), called ‘reactive’ ‘deserted’. These histologically definable tissue states exhibit strong relationships with immunity, subtypes, differentiation, treatment response. Here, we set out define...