A5004957388- Cancer Genomics and Diagnostics
- Evolution and Genetic Dynamics
- Genetic factors in colorectal cancer
- Breast Cancer Treatment Studies
- Single-cell and spatial transcriptomics
- Gene expression and cancer classification
- Evolutionary Game Theory and Cooperation
- Epigenetics and DNA Methylation
- Gene Regulatory Network Analysis
- Acute Ischemic Stroke Management
- Bioinformatics and Genomic Networks
- Lung Cancer Treatments and Mutations
- Pharmacogenetics and Drug Metabolism
- Mathematical and Theoretical Epidemiology and Ecology Models
- Mathematical Biology Tumor Growth
- BRCA gene mutations in cancer
- Advanced Biosensing Techniques and Applications
- Cancer therapeutics and mechanisms
- vaccines and immunoinformatics approaches
- AI in cancer detection
- Cell Image Analysis Techniques
- Neonatal and fetal brain pathology
- Genetics, Bioinformatics, and Biomedical Research
- Bacteriophages and microbial interactions
- Colorectal Cancer Treatments and Studies
Hospital for Sick Children
2024-2025
Institute of Cancer Research
2017-2022
Cancer Institute (WIA)
2022
Genomics (United Kingdom)
2017-2021
Case Western Reserve University
2019
Moffitt Cancer Center
2014-2019
University of Oxford
2014-2019
University School
2019
Cancer Research UK
2017
Abstract Antibiotic resistance represents a growing health crisis that necessitates the immediate discovery of novel treatment strategies. One such strategy is identification collateral sensitivities, wherein evolution under first drug induces susceptibility to second. Here, we report sequential regimens derived from in vitro experiments may have overstated therapeutic benefit, predicting collaterally sensitive response where cross-resistance ultimately occurs. We quantify likelihood this...
Abstract Genetic and epigenetic variation, together with transcriptional plasticity, contribute to intratumour heterogeneity 1 . The interplay of these biological processes their respective contributions tumour evolution remain unknown. Here we show that genetic ancestry only infrequently affects gene expression traits subclonal in colorectal cancer (CRC). Using spatially resolved paired whole-genome transcriptome sequencing, find the majority variation is not strongly heritable but rather...
Abstract Colorectal malignancies are a leading cause of cancer-related death 1 and have undergone extensive genomic study 2,3 . However, DNA mutations alone do not fully explain malignant transformation 4–7 Here we investigate the co-evolution genome epigenome colorectal tumours at single-clone resolution using spatial multi-omic profiling individual glands. We collected 1,370 samples from 30 primary cancers 8 concomitant adenomas generated 1,207 chromatin accessibility profiles, 527 whole...
The increasing rate of antibiotic resistance and slowing discovery novel treatments presents a growing threat to public health. Here, we consider simple model evolution in asexually reproducing populations which considers adaptation as biased random walk on fitness landscape. This associates the global properties landscape with algebraic Markov chain transition matrix allows us derive general results non-commutativity irreversibility natural selection well cycling strategies. Using this...
Abstract Drug resistance mediated by clonal evolution is arguably the biggest problem in cancer therapy today. However, evolving to one drug may come at a cost of decreased fecundity or increased sensitivity another drug. These evolutionary trade-offs can be exploited using ‘evolutionary steering’ control tumour population and delay resistance. recapitulating dynamics experimentally remains challenging. Here, we present an approach for steering based on combination single-cell barcoding,...
Drug resistance remains an elusive problem in cancer therapy, particularly for novel targeted therapies. Much work is focused upon the development of arsenal therapies, towards oncogenic driver genes such as ALK-EML4, to overcome inevitable that develops over time. Currently, after failure first line ALK TKI another administered, though collateral sensitivity not considered. To address this, we evolved rearranged non-small cell lung (H3122) a panel 4 TKIs, and performed analysis. All...
Blockade of epidermal growth factor receptor (EGFR) causes tumor regression in some patients with metastatic colorectal cancer (mCRC). However, residual disease reservoirs typically remain even after maximal response to therapy, leading relapse. Using patient-derived xenografts (PDXs), we observed that mCRC cells surviving EGFR inhibition exhibited gene expression patterns similar those a quiescent subpopulation normal intestinal secretory precursors Paneth cell characteristics. Compared...
BackgroundGlioblastoma is the most common and aggressive adult brain malignancy against which conventional surgery chemoradiation provide limited benefit. Even when a good treatment response obtained, recurrence inevitably occurs either locally (∼80%) or distally (∼20%), driven by cancer clones that are often genomically distinct from those in primary tumour. Glioblastoma cells display characteristic infiltrative phenotype, invading surrounding tissue spreading across whole brain. Cancer...
Abstract Both normal tissue development and cancer growth are driven by a branching process of cell division mutation accumulation that leads to intra-tissue genetic heterogeneity. However, quantifying somatic evolution in humans remains challenging. Here, we show multi-sample genomic data from single time point tissues contains information on single-cell divisions. We present new theoretical framework that, applied whole-genome sequencing healthy cancer, allows inferring the rate...
Cancers are complex dynamic systems that undergo evolution and selection. Personalized medicine approaches in the clinic increasingly rely on predictions of tumour response to one or more therapies; these complicated by inevitable tumour. Despite enormous amounts data mutational status cancers numerous therapies developed recent decades target mutations, many treatments fail after a time due development resistance The emergence resistant phenotypes is not easily predicted from genomic data,...
Abstract Circulating tumour DNA (ctDNA) allows tracking of the evolution human cancers at high resolution, overcoming many limitations tissue biopsies. However, exploiting ctDNA to determine how a patient’s cancer is evolving in order aid clinical decisions remains difficult. This because mix fragmented alleles, and contribution different deposits largely unknown. Profiling almost invariably requires prior knowledge what genomic alterations track. Here, we leverage on rapid autopsy programme...
Introduction: The burden of disease from pediatric arterial ischemic stroke (AIS) includes non-visible disability in the form mental health conditions such as depression and anxiety which impact quality life children families affected by stroke. Objectives: To determine scale phenomenon AIS population a large single-center study, to educate clinicians about this significant risk survivors. Methods: A retrospective analysis prospective cohort school-aged diagnosed with AIS, enrolled between...
Nongenetic variation in phenotypes, or bet-hedging, has been observed as a driver of drug resistance both bacterial infections and cancers. Here, we study how bet-hedging emerges genotype-phenotype (GP) mapping through simple interaction model: molecular switch. We use chemical reaction networks to implement stochastic switches that map gene products investigate the impact structurally distinct mappings on evolution phenotypic heterogeneity. Bet-hedging naturally within this model, is robust...
The most significant prognostic factor in early breast cancer is lymph node involvement. This stage between localized and systemic disease key to understanding progression; however, our knowledge of the evolution malignant invasion remains limited, as currently available data are derived from primary tumors.
Intra-tumour heterogeneity is a leading cause of treatment failure and disease progression in cancer. While genetic mutations have long been accepted as primary mechanism generating this heterogeneity, the role phenotypic plasticity becoming increasingly apparent driver intra-tumour heterogeneity. Consequently, understanding resistance key component improving cancer therapy. We develop mathematical model stochastic phenotype switching that tracks evolution drug-sensitive drug-tolerant...
Time from stroke onset to hospital arrival determines treatment and impacts outcome. Structural, socioeconomic, environmental factors are associated with health inequity onset-to-arrival in adult stroke. We aimed assess the association between a pediatric comprehensive center.
Abstract Immune therapies have shown promise in a number of cancers, and clinical trials using the anti-PD-L1/PD-1 checkpoint inhibitor lung cancer been successful for patients. However, some patients either do not respond to treatment or recurrence after an initial response. It is clear which might fall into these categories what mechanisms are responsible failure. To explore different underlying biological resistance, we created spatially explicit mathematical model with modular framework....
Abstract Drug resistance mediated by clonal evolution is arguably the biggest problem in cancer therapy today. However, evolving to one drug may come at a cost of decreased growth rate or increased sensitivity another due evolutionary trade-offs. This weakness can be exploited clinic using an approach called ‘evolutionary herding’ that aims controlling tumour cell population delay prevent resistance. recapitulating dynamics experimentally remains challenging. Here we present novel for...
Abstract Antibiotic resistance represents a growing health crisis that necessitates the immediate discovery of novel treatment strategies. One such strategy is identification collateral sensitivities, wherein evolution under first drug induces susceptibility to second. Here, we report sequential regimens derived from in vitro experiments may have overstated therapeutic benefit, predicting collaterally sensitive response where cross ultimately occurs. We quantify likelihood this phenomenon by...
A morbidostat is a bioreactor that uses antibiotics to control the growth of bacteria, making it well-suited for studying evolution antibiotic resistance. However, morbidostats are often too expensive be used in educational settings. Here we present low-cost called EVolutionary biorEactor (EVE) can built by students with minimal engineering and programming experience. We describe how validated EVE real classroom setting evolving replicate Escherichia coli populations under chloramphenicol...
Abstract The vast majority of cancer next-generation sequencing data consist bulk samples composed mixtures and normal cells. To study tumor evolution, subclonal reconstruction approaches based on machine learning are used to separate subpopulation cells reconstruct their ancestral relationships. However, current entirely data-driven agnostic evolutionary theory. We demonstrate that systematic errors occur in if evolution is not accounted for, those increase when multiple taken from the same...
Abstract Colorectal malignancies are a leading cause of cancer death. Despite large-scale genomic efforts, DNA mutations do not fully explain malignant evolution. Here we study the co-evolution genome and epigenome colorectal tumours at single-clone resolution using spatial multi-omic profiling individual glands. We collected 1,373 samples from 30 primary cancers 9 concomitant adenomas generated 1,212 chromatin accessibility profiles, 527 whole-genomes 297 whole-transcriptomes. found...