The workshop on Cell Dynamics and Chromosomal Stability will exploredynamic cellular, subcellular and molecular mechanisms that underpinchromosomal stability. We will also be introducing the imaging facilitieswithin the Center for Cell Dynamics (CCD) and Al-guided SpinX software for object tracking (now available via Zeiss arivis Cloud). The event is supported by Research England Regional Investment Funding.
14:00-14:10 Welcome opening remarks and Keynote speaker short introduction (Prof. Viji Draviam)
Session 1 (14:00-16:00) Venue: Room 0.14, iQ East Court (Scape)
14:10-14:55 Prof. Kozo Tanaka (Keynote speaker,Tohoku University, Japan) Chromosomal instability caused by alterations in chromosome dynamics. Most cancer cells exhibit chromosomal instability, a condition in which chromosome missegregation occurs at high rates. Among the causes of chromosomal instability, inefficient correction of erroneous kinetochore-microtubule attachments plays a pivotal role. We recently found the previously unappreciated role of chromosome oscillation, an iterative chromosome motion during metaphase, in the correction of erroneous kinetochore-microtubule attachments. Chromosome oscillation facilitates the metaphase phosphorylation of Hec1, a kinetochore protein that binds to microtubules, by Aurora A kinase on the spindle. The phosphorylation of Hec1 reduces its affinity to microtubules, which promotes the correction of erroneous kinetochore-microtubule attachments. Importantly, chromosome oscillation is attenuated in cancer cells with chromosomal instability compared to non-transformed cells. The attenuated chromosome oscillation and the resulting reduced Hec1 phosphorylation may be a cause of chromosomal instability in cancer cells. Interestingly, chromosome oscillation and Hec1 phosphorylation are suppressed in non-transformed cells in the presence of culture supernatants of cancer cells with chromosomal instability. We found that antioxidant metabolites present in the cancer cell culture supernatants are responsible for the reduced Hec1 phosphorylation, suggesting the possibility that the antioxidant metabolites may reduce oxidative stress during mitosis, which is required for mitotic fidelity in non-transformed cells.
14:55-15:25 Dr. Pilar Cacheiro (Queen Mary University of London, UK) Genes essential for organism development in humans. Human essential genes are often described as those required for cell proliferation in cancer or stem cell lines (cellular lethal/essential). Mouse knockouts are subject to comprehensive phenotypic screens that include embryonic and postnatal viability assessment. This results in genes being associated with lethal outcomes and classified as developmental lethal/essential. In order to identify genes essential for human organism development, we can systematically review clinical reports documenting instances of early death associated with Mendelian, single-gene disorders. In doing so, we found evidence of pre-infant death phenotypes for 975 genes, including 192 linked specifically to prenatal death. This number is likely an underestimation, given the information we have from mouse screenings and the potential absence of molecular diagnosis for many confirmed miscarriages and pregnancy losses. Determining whether a gene is essential depends on several factors, including the level of organisation, species, thresholds for quantitative effect scores or developmental stage at which death occurs. Integrating multiple sources of evidence allows us to understand the full spectrum of intolerance to loss-of-function variation.
15:25-15:45 Martin Gonzalez Fernandez (University of Bern, Switzerland) Docetaxel response in BRCA1; p53-deficient mammary tumor cells is affected by Huntingtin and BAP1. Taxanes are frequently used anti-cancer drugs known to kill tumor cells by inducing mitotic aberrations and segregation defects. A defining feature of specific cancers, notably triple-negative breast cancer (TNBC) and particularly those deficient in BRCA1, is chromosomal instability (CIN). Here, we focused on understanding the mechanisms of docetaxel-induced cytotoxicity, especially in the context of BRCA1-deficient TNBC. Using functional genetic screens in CIN+ cells, we identified genes that mediate docetaxel response and found a novel interaction between Huntingtin (HTT) and BRCA1 associated protein-1 (BAP1). We employed Brca1-/-;p53-/- mammary tumor cells, derived from genetically engineered mouse tumors that closely mimic the human disease, to investigate the role of these genes in CIN+ BRCA1-deficient cells. Specifically, we observed that loss of HTT sensitizes CIN+ BRCA1-deficient mammary tumor cells to docetaxel by inducing alterations of the mitotic spindle; while BAP1 depletion protected cells against these spindle aberrations. Our findings shed light on the roles of HTT and BAP1 in controlling mitotic spindle dynamics, specifically in the absence of BRCA1. This affects the response to microtubule-targeting agents and suggests that further studies of the interaction of these genes with the mitotic spindle may provide useful insights on how to target CIN+ cells, particularly in the challenging therapeutic landscape of BRCA1-deficient TNBC.
15:45-16:00 Coffee and Discussion
Session 2 (16:00-18:00) Venue: David Sizer LT, Bancroft Building
16:00-16:30 Short break - Coffee/Tea/Sweets (Bancroft foyer)
16:30-17:00 Dr. Binghao Chai (Queen Mary University of London, UK) Title TBC. Abstract TBC.
17:00-17:20 Abbas Khan Rayabat Khan (Queen Mary University of London, UK) Crop and Couple: Cardiac Image segmentation using Interlinked Specialist Networks. Diagnosis of cardiovascular disease using automated methods often relies on the critical task of cardiac image segmentation. We propose a novel strategy that performs segmentation using specialist networks that focus on a single anatomy (left ventricle, right ventricle, or myocardium). Given an input long-axis cardiac MR image, our method performs a ternary segmentation in the first stage to identify these anatomical regions, followed by cropping the original image to focus subsequent processing on the anatomical regions. The specialist networks are coupled through an attention mechanism that performs cross-attention to interlink features from different anatomies, serving as a soft relative shape prior. Central to our approach is an additive attention block (E-2A block), which is used throughout our architecture thanks to its efficiency. The pre-trained models, source code, and implementation will be publicly available. (Accepted at ISBI 2024, Greece)
17:20-17:40 Dr. Chengchen Wu (Queen Mary University of London, UK) 53BP1-GFP: A framework for FRAP in the SR regime. 53BP1 forms liquid condensates and facilitates long-range DNA end-joining but the underlying mechanism has remained elusive. CRISPR-engineered insertion of a GFP tag in the endogenous loci of TP53BP1 revealed nuclear subcompartments of 53BP1 foci that show differential 53BP1 protein mobilities. 53BP1-GFP foci that remain as a single compartment are stationary and behave differently from those that resolve into multiple compartments. Using FRAP analysis in the Super-Resolution (SR) regime, we find that 53BP1 foci showing multiple compartments of varying protein mobilities are more active than others that remain stationary as a single compartment.
17:40-17:45 Closing remarks of workshop (Prof. Viji Draviam, Thank-you note).
17:45-18:00 Coffee and Discussion