David Cook

Mount Sinai Hospital, Toronto

Ovarian cancer is a complex disease with multiple subtypes, each having distinct histopathologies and variable responses to treatment. This review highlights the technological milestones and the studies that have applied them to change our definitions of ovarian cancer. Over the past 50 years, technologies such as microarrays and next-generation se...

Epithelial–mesenchymal plasticity contributes to many biological processes, including tumor progression. Various epithelial–mesenchymal transition (EMT) responses have been reported and no common, EMT-defining gene expression program has been identified. Here, we have performed a comparative analysis of the EMT response, leveraging highly multiplex...

Epithelial-mesenchymal plasticity (EMP) contributes to tumour progression, promoting therapy resistance and immune cell evasion. Definitive molecular features of this plasticity have largely remained elusive due to the limited scale of most studies. Leveraging scRNA-seq data from 160 tumours spanning 8 different cancer types, we identify expression...

The ovarian surface epithelium (OSE) is a monolayer of epithelial cells surrounding the ovary that ruptures during each ovulation to allow release of the oocyte. This wound is quickly repaired, but mechanisms promoting repair are poorly understood. The contribution of tissue-resident stem cells in the homeostasis of several epithelial tissues is wi...

During late lung development, alveolar and microvascular development is finalized to enable sufficient gas exchange. Impaired late lung development manifests as bronchopulmonary dysplasia (BPD) in preterm infants. Single-cell RNA sequencing (scRNA-seq) allows for assessment of complex cellular dynamics during biological processes, such as developme...

The fish gill is a multifunctional organ involved in numerous physiological processes, such as gas exchange and sensing of hypoxia by respiratory chemoreceptors, called neuroepithelial cells (NECs). Many studies have focused on zebrafish (Danio rerio) to investigate the structure, function and development of the gills, yet the transcriptomic profil...

Alzheimer′s Disease (AD) is the most common form of dementia with progressive cognitive deficits and mood disorders (Knopman et al., 2021). Recent studies have associated AD pathology with the impairment of adult neurogenesis, as indicated by impaired neural stem cell (NSCs) homeostasis (Bond et al., 2015). Recent work has further associated AD pro...

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer with an imperative need for new treatments. Immunotherapy has had marked success in some cancer types; however, clinical trials studying the efficacy of immune checkpoint inhibitors for the treatment of EOC benefited less than 15% of patients. Given that EOC develops from multipl...

Trogocytosis modulates immune responses, with still unclear underlying molecular mechanisms. Using leukemia mouse models, we found that lymphocytes perform trogocytosis at high rates with tumor cells. While performing trogocytosis, both Natural Killer (NK) and CD8+ T cells acquire the checkpoint receptor PD-1 from leukemia cells. In vitro and in vi...

Background Invasive lobular carcinoma (ILC) is the second most common type of breast cancer. As few tools exist to study ILC metastasis, we isolated ILC cells with increased invasive properties to establish a spontaneously metastasising xenograft model. Methods MDA-MB-134VI ILC cells were placed in transwells for 7 days. Migrated cells were isolat...

Epithelial-mesenchymal plasticity (EMP) reflects the capacity of cells to interconvert between epithelial and mesenchymal phenotypes. In cancer, these dynamics ultimately contribute to disease progression. Despite decades of study, a consistent molecular definition of this plasticity remains elusive because of its inherent variability. The advent o...

Late lung development is a period of alveolar and microvascular formation, which is pivotal in ensuring sufficient and effective gas exchange. Defects in late lung development manifest in premature infants as a chronic lung disease named bronchopulmonary dysplasia (BPD). Numerous studies demonstrated the therapeutic properties of exogenous bone mar...

Epithelial-mesenchymal plasticity (EMP) contributes to tumor progression, promoting therapy resistance and immune cell evasion. Definitive molecular features of this plasticity have largely remained elusive due to the limited scale of most studies. Leveraging single-cell RNA sequencing data from 266 tumors spanning eight different cancer types, we...

Rationale Human lung development has been mainly described in morphologic studies and the potential underlying molecular mechanisms were extrapolated from animal models. Therefore, there is a need to gather knowledge from native human lung tissue. In this study we describe changes at a single-cell level in human fetal lungs during the pseudoglandul...

Background Breast cancer is a highly heterogeneous disease with multiple drivers and complex regulatory networks. Periostin (Postn) is a matricellular protein involved in a plethora of cancer types and other diseases. Postn has been shown to be involved in various processes of tumor development, such as angiogenesis, invasion, cell survival and met...

The protein Lgl1 is a key regulator of cell polarity. We previously showed that Lgl1 is inactivated by hyperphosphorylation in glioblastoma as a consequence of PTEN tumour suppressor loss and aberrant activation of the PI 3-kinase pathway; this contributes to glioblastoma pathogenesis both by promoting invasion and repressing glioblastoma cell diff...

Rational Endothelial damage plays a central role in acute lung injury, and regeneration of lung vascular endothelium is required for its resolution in preclinical models. Objectives We sought to define the cellular and molecular mechanisms underlying lung microvascular regeneration in acute lung injury induced by lung endothelial cell ablation. M...

Late lung development is a period of alveolar and microvascular formation, which is pivotal in ensuring sufficient and effective gas exchange. Defects in late lung development manifest in premature infants as a chronic lung disease named bronchopulmonary dysplasia (BPD). Numerous studies demonstrated the therapeutic properties of exogenous bone mar...

Macrophage autophagy is a highly anti-atherogenic process that promotes the catabolism of cytosolic lipid droplets (LDs) to maintain cellular lipid homeostasis. Selective autophagy relies on tags such as ubiquitin and a set of selectivity factors including selective autophagy receptors (SARs) to label specific cargo for degradation. Originally desc...

The protein Lgl1 has key roles in the regulation of cell polarity. We have shown that Lgl1 is inactivated by hyperphosphorylation in glioblastoma as a consequence of PTEN loss and aberrant activation of the PI 3-kinase pathway; this contributes to glioblastoma pathogenesis both by promoting invasion and repressing glioblastoma cell differentiation....

Obesity is a major public health burden worldwide and is characterized by chronic low-grade inflammation driven by the cooperation of the innate immune system and dysregulated metabolism in adipose tissue and other metabolic organs. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a central regulator of inflammatory cell function t...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Epithelial-mesenchymal heterogeneity is ubiquitous among epithelial tissues and the reversible transition (EMT) between these two states provides ovarian cancer cells with plasticity to promote metastasis and resistance to chemotherapy. While extensively studied, no common, EMT-defining expression program has been identified. Leveraging multiplexed...

The ovarian surface epithelium (OSE) is a monolayer of epithelial cells covering the surface of the ovary. During ovulation, the OSE is ruptured to allow release of the oocyte. This wound is quickly repaired, but mechanisms of this repair are poorly understood. The contribution of tissue-resident stem cells in the homeostasis of several epithelial...

HER2 is overexpressed in 20–30% of all breast cancers and is associated with an invasive disease and poor clinical outcome. The Ste20-like kinase (SLK) is activated downstream of HER2/Neu and is required for efficient epithelial-to-mesenchymal transition, cell cycle progression, and migration in the mammary epithelium. Here we show that loss of SLK...

In embryonic stem cells (ESCs), the SWI/SNF, CHD, and INO80 families of ATP-dependent chromatin remodellers have been implicated in maintaining pluripotency-associated gene expression. At the time of this study, the importance of ISWI family remodellers had yet to be defined, and we had sought to assess their involvement. During this time, Barisic...

Over the past two decades, the mammalian Ste20-like kinase (SLK) has been characterized for its role in regulating cellular migration, proliferation and apoptosis in fibroblasts and myoblasts. In mammary epithelial cells, SLK has been shown to be required for efficient epithelial-to-mesenchymal transition and to be activated downstream of the HER2/...

The fifth Canadian Cancer Research Conference (CCRC) took place 3-5 November 2019 in Ottawa, Ontario. With nearly 1000 participants, scientists, oncologists, community members, and patients gathered together to share knowledge, foster collaborations, and fuel the future of cancer research in Canada. The scientific program included three plenary ses...

During late lung development alveolar and microvascular development is finalized to enable sufficient gas exchange. Impaired late lung development manifests as bronchopulmonary dysplasia (BPD) in preterm infants. Single-cell RNA sequencing (scRNA-seq) allows for assessment of complex cellular dynamics during biological processes, such as developmen...

Purpose: The ovarian cancer risk factors of age and ovulation are curious since ovarian cancer incidence increases in postmenopausal women, long after ovulations have ceased. To determine how age and ovulation underlie ovarian cancer risk, we assessed the effects of these risk factors on the ovarian microenvironment. Experimental design: Aged C5...

Epithelial-mesenchymal (E/M) heterogeneity is ubiquitous within all epithelial tissues and the reversible transition between these two states provides cells with plasticity that contributes to organogenesis in the developing embryo, tissue homeostasis in adults, and tumour progression. While the epithelial-mesenchymal transition (EMT) has been exte...

The ovarian surface epithelium (OSE) is a monolayer of cells surrounding the ovary that is ruptured during ovulation. After ovulation, the wound is repaired, however this process is poorly understood. In epithelial tissues, wound repair is mediated by an epithelial-to-mesenchymal transition (EMT). Transforming Growth Factor Beta-1 (TGFβ1) is a cyto...

Author summary Women who take estrogen replacement therapy are at higher risk of developing ovarian cancer. When ovarian epithelial cells are exposed to estrogen, there is a heterogeneous cellular response, with some cells appearing unaffected, while others become disorganized and grow at accelerated rates consistent with pre-cancerous cells. This...

TGFB1 signalling in OSE. Left: PCA of OSE cells coloured by a gene set score of “TGFB1 Signalling” from the Molecular Signatures Database. Right: The distribution of gene set scores between the three clusters. Horizontal bar represents the median value for each group. (TIF)

Differential expression results between Clusters 1 (rightmost cells) and 2 (leftmost cells; k = 2). (XLS)

Assessing E2 responsiveness. Top row: PCA of OSE cells, coloured by the logged counts of Esr1 (left), Esr2 (middle), and a gene set score for the “Early Estrogen Response” gene set from the Molecular Signatures Database (right). Bottom row: Plot showing the distribution of expression levels (logged counts) within cluster. Horizontal bar represents...

Staining control with no primary antibody and original images for LTBP2 IF. Original merged and unmerged z-stack maximum intensity projections from the DAPI, AF555 (Actin), and AF488 (LTBP2) channels for LTBP2 staining. Scale bar = 15μm. (TIF)

Full list of GO Terms and KEGG Pathways associated with Clusters 1(rightmost cells) and 2 (leftmost cells; k = 2). (XLS)

Pseudotime branch-dependent gene expression results. (XLS)

List and details for antibodies used. (XLS)

scRNA-Seq quality control and imputation. (A) Boxplots of each library’s transcript counts relative to number of cells observed in corresponding capture sites. (B) Scatter plot of Col1a2 (mesenchymal gene) and Krt19 (epithelial gene) expression levels (left) and PCA of OSE cells (right) before imputation and (C) following imputation using MAGIC. (T...

Principal component analysis of control and E2-treated OSE. Scree plot (left) for the principal component analysis highlighting the fraction of total variance explained by the first few principal components, along with PCA plots of PC1 vs. PC3 (middle) and PC4 (right). (TIF)

Clustering patterns with increasing k. PCA of OSE cells, coloured by cluster. Increasing the number of clusters (k parameter) does not separate the control and E2-treated cells of the putative E2-unresponsive population. (TIF)

Staining control with no primary antibody and original images for PTGIS IF. Original merged and unmerged z-stack maximum intensity projections from the DAPI, AF555 (Actin), and AF488 (PTGIS) channels for PTGIS staining. Scale bar = 15μm. (TIF)

Staining control with no primary antibody and original images for IGFBP5 IF. Original merged and unmerged z-stack maximum intensity projections from the DAPI, AF555 (Actin), and AF488 (IGFBP5) channels for IGFBP5 staining. Scale bar = 15μm. (TIF)

IHC staining controls. Tissue sections prepared with no primary antibodies for LTBP2, IGFBP5, PTGIS, and GREB1 in the ovary and fallopian tube epithelial (FTE). (TIF)

Area under receiver operator characteristic (ROC) curves. (XLS)

Full list of GO Terms and KEGG Pathways associated with each cluster of branch-dependent genes. (XLS)

Differential expression results between Clusters 2 and 3 (k = 3). (XLS)

Full list of GO Terms and KEGG Pathways associated with Clusters 2 and 3 (k = 3). (XLS)

The Androgen Receptor (AR) has recently garnered a lot of attention as a potential biomarker and therapeutic target in hormone-dependent cancers, including breast cancer. However, several inconsistencies exist within the literature as to which subtypes of breast cancer express AR or whether it can be used to define its own unique subtype. Here, we...

Ubiquitin and ubiquitin-like molecules are attached to and removed from cellular proteins in a dynamic and highly regulated manner. Deubiquitinating enzymes are critical to this process, and the genetic catalogue of deubiquitinating enzymes expanded greatly over the course of evolution. Extensive functional redundancy has been noted among the 93 me...