Biology subjects

Jacobson, D. H.

Publications and source records attributed to Jacobson, D. H..

4 recordsLinked to original sources

bioRxiv2026

Polyclonal and single clonal patient-derived organoid models of Barrett oesophagus and oesophageal adenocarcinoma establish a platform for the analysis of heterogeneity in disease progression and therapy response

SUMMARY/ABSTRACTOesophageal adenocarcinoma (OAC) is a major cause of morbidity and mortality. OAC and its precursor, Barrett oesophagus (BO), are defined by substantial early heterogeneity, complicating prevention and treatment of OAC and remaining poorly recapitulated by current in vitro and animal model systems. We have generated 116 patient- and healthy donor-derived organoids (PDOs) spanning normal oesophagogastric tissue, BO and OAC. These PDOs capture population diversity and recapitulate phenotypic, genomic and transcriptomic features of their respective disease stages. We develop a single cell-derived clonal organoid approach and show that this enables us to capture the heterogeneity and isolate high-risk, subclonal populations that are difficult to discern and maintain in bulk PDO cultures. Using this platform, we demonstrate functional importance of this biobank across the pre-malignant to invasive disease spectrum, including a role for BO in shaping fibroblast phenotype within assembloids, and diverse responses of OAC to chemotherapy, radiotherapy and targeted CDK4/6 inhibition. HIGHLIGHTSO_LIPatient- and healthy donor-derived organoids (PDOs) provide a functional platform of disease progression and heterogeneity across normal gastric, non-dysplastic and dysplastic Barrett oesophagus (BO) and oesophageal adenocarcinoma (OAC). C_LIO_LIWe provide a quantitative phenotypic and molecular framework to assess the provenance and fidelity of each PDO model given the heterogeneity of this disease. C_LIO_LIPDOs recapitulate key features of non-dysplastic and dysplastic BO, as well as invasive OAC. C_LIO_LISingle cell-derived clonal organoids (sc-organoids) isolate and maintain high-risk subclonal populations. C_LIO_LIOAC PDOs mirror known population level variation in response to systemic anti-cancer therapies. C_LI

cancer biology↗

bioRxiv2023

Multi-scale characterisation of homologous recombination deficiency in breast cancer

BackgroundHomologous recombination is a robust, broadly error-free mechanism of double strand break repair, and deficiencies cause reliance on alternative repair processes, leading to sensitivity to PARP inhibitors. Patients displaying homologous recombination deficiency can be identified using mutational signatures. However, these patterns are difficult to reliably infer from exome sequencing. Additionally, as mutational signatures are a historical record of mutagenic processes, this limits their utility in describing the current status of a tumour. ResultsHere, we apply two methods for classifying homologous recombination deficiency in breast cancer to explore the features and heterogeneity associated with this phenotype. Firstly, we apply a likelihood-based method which leverages small insertions and deletions to improve classification of homologous recombination deficiency in exome sequenced breast cancers. We find that whilst BRCA+ homologous recombination deficient samples display strong similarities to those harbouring BRCA defects, they deviate in microenvironmental features such as hypoxic signalling. Secondly, using this classification we develop a 228-gene transcriptional signature which simultaneously characterises homologous recombination deficiency and BRCA1/2-defect status, and is linked with PARP inhibitor response. Finally, we apply this signature to single-cell RNA-sequenced breast cancer cohorts to study homologous recombination deficiency at single cell resolution and demonstrate that these cells present a distinct milieu of interactions with immune cells in their microenvironment compared to their HR proficient counterparts, which could inform checkpoint blockade for HRD tumours. ConclusionsWe apply multi-scale approaches to characterise homologous recombination deficiency in breast cancer through the development of mutational and transcriptional signatures. We show that indels, even at low levels, can improve homologous recombination deficiency classification. Additionally, we demonstrate the heterogeneity of homologous recombination deficiency, especially in relation to BRCA status, and show that indications of this feature can be captured at a single-cell level, enabling further investigations into interactions between DNA repair deficient cells and their tumour microenvironment.

genomics↗

bioRxiv2021

Genomic hallmarks of cellular dormancy in cancer and therapeutic implications

Therapy resistance in cancer is often driven by a subpopulation of cells that are temporarily arrested in a non-proliferative G0 state, which is difficult to capture and whose mutational drivers remain largely unknown. We developed methodology to robustly identify this state from transcriptomic signals and characterised its prevalence and genomic constraints in solid primary tumours. We show that G0 arrest preferentially emerges in the context of more stable, less mutated genomes which maintain TP53 integrity and lack the hallmarks of DNA damage repair deficiency, while presenting increased APOBEC mutagenesis. We employ machine learning to uncover novel genomic dependencies of this process and validate the role of the centrosomal gene CEP89 as a modulator of proliferation/G0 arrest capacity. Lastly, we demonstrate that G0 arrest underlies unfavourable responses to various therapies exploiting cell cycle, kinase signalling and epigenetic mechanisms in single cell data, and propose a G0 arrest transcriptional signature that is linked with therapeutic resistance and can be used to further study and clinically track this state.

cancer biology↗

bioRxiv2021

Pan-cancer survey of tumour mass dormancy and underlying mutational processes

Tumour mass dormancy is the key intermediate step between immune surveillance and cancer progression, yet due to its transitory nature it has been difficult to capture and characterise. Little is understood of its prevalence across cancer types and of the mutational background that may favour such a state. While this balance is finely tuned internally by the equilibrium between cell proliferation and cell death, the main external factors contributing to tumour mass dormancy are immunological and angiogenic. To understand the genomic and cellular context in which tumour mass dormancy may develop, we comprehensively profiled signals of immune and angiogenic dormancy in 9,631 cancers from the Cancer Genome Atlas and linked them to tumour mutagenesis. We find evidence for immunological and angiogenic dormancy-like signals in 16.5% of bulk sequenced tumours, with a frequency of up to 33% in certain tissues. Mutations in the CASP8 and HRAS oncogenes were positively selected in dormant tumours, suggesting an evolutionary pressure for controlling cell growth/apoptosis signals. By surveying the mutational damage patterns left in the genome by known cancer risk factors, we found that ageing-induced mutations were relatively depleted in these tumours, while patterns of smoking and defective base excision repair were linked with increased tumour mass dormancy. Furthermore, we identified a link between APOBEC mutagenesis and dormancy, which comes in conjunction with immune exhaustion and may partly depend on the expression of the angiogenesis regulator PLG as well as interferon and chemokine signals. Tumour mass dormancy also appeared to be impaired in hypoxic conditions in the majority of cancers. The microenvironment of dormant cancers was enriched in cytotoxic and regulatory T cells, as expected, but also in macrophages and showed a reduction in inflammatory Th17 signals. Finally, tumour mass dormancy was linked with improved patient survival outcomes. Our analysis sheds light onto the complex interplay between dormancy, exhaustion, APOBEC activity and hypoxia, and sets directions for future mechanistic explorations.

cancer biology↗