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Item Modelling the Role of the Microbiome in Infection Triggered Acute Lymphoblastic Leukaemia(Institute of Cancer Research (University Of London), 2026-05-13)B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common childhood malignancy in developed countries, with genetic diversity dominated by ETV6::RUNX1 fusion and hyperdiploidy subtypes. BCP-ALL is initiated in utero but requires additional postnatal genetic events for overt disease development. Our 'delayed infection' hypothesis proposes that insufficient microbial exposure early in life leads to abnormal immune responses, increasing the risk of leukaemia, while early microbial exposure provides protection. We investigated this hypothesis using an ETV6::RUNX1 transgenic mouse model. Transgenic mice transferred from a specific pathogen-free (SPF1, 'clean') facility to an endemic microbe-rich (SPF2, 'dirty') environment at 5–8 weeks of age developed BCP-ALL with approximately 25% penetrance. Interestingly, mice born and raised in the 'dirty' environment before fumigation did not develop leukaemia. Moreover, those moved to sanitised SPF2 conditions post-fumigation also did not develop leukaemia. Microbiome analyses revealed distinct gut microbial compositions between housing facilities and between pre- and post-fumigation periods; mice from pre-fumigation 'dirty' housing exhibited higher microbial diversity, including abundant anti-inflammatory, short-chain fatty acid-producing genera. Our research also explored gut microbiome stability by studying the impact of ageing, antibiotics, and microbial transplantation methods. Faecal microbiota transplantation (FMT) experiments confirmed that the gut microbiome could be significantly altered. This work demonstrates that exposure to common endemic and occasional sporadic microbes can promote BCP-ALL initiated by the ETV6::RUNX1 gene fusion, highlighting murine norovirus as a potential trigger for ALL in this model. Our findings support the 'delayed infection' hypothesis, indicating early-life microbial exposure may protect against infection driven leukaemia, emphasising the potential role of the gut microbiome in leukaemia risk and prevention strategies. Finally, preliminary human microbiome analysis revealed that healthy control children showed significantly higher gut microbial diversity than children with ALL, independent of age and sex. Beta diversity analysis also indicated distinct microbial community structures between healthy controls and ALL groups, supporting a potential protective role of a diverse microbiome in early life.Item Longitudinal monitoring of circulating tumor DNA to detect relapse early and predict outcome in early breast cancer.(SPRINGER, 2025-02-01)PURPOSE: Detection of molecular residual disease (MRD) allows for the identification of breast cancer patients at high-risk of recurrence, with the potential that early initiation of treatment at early stages of relapse could improve patient outcomes. The Invitae Personalized Cancer Monitoring™ assay (PCM) is a newly developed next-generation sequencing approach that utilizes up to 50 patient-specific, tumor-informed DNA variants, to detect circulating tumor DNA (ctDNA). The ability of the PCM assay to detect MRD before clinical relapse was evaluated. METHODS: The cohort included 61 female patients with high-risk breast cancer who underwent neoadjuvant chemotherapy. Plasma samples were collected before and during neoadjuvant therapy, after surgery and during monitoring. PCM was used to detect ctDNA at each time point. RESULTS: The sensitivity to detect ctDNA in plasma from patients who relapsed during the monitoring phase was 76.9% (10/13). Specificity and positive predictive values were both 100% with all (10/61, 16%) of the patients who had ctDNA detected during the monitoring phase subsequently relapsing. Detection of ctDNA during monitoring was associated with a high-risk of future relapse (HR 37.2, 95% CI 10.5-131.9, p < 0.0001), with a median lead-time from ctDNA detection to clinical relapse of 11.7 months. CONCLUSION: PCM detected ctDNA in patients who relapsed with a long lead-time over clinical relapse, shows strong association with relapse-free survival and may be used to identify patients at high-risk for relapse, allowing for earlier intervention.Item Extensive and systematic rewiring of histone post-translational modifications in cancer model systems.(OXFORD UNIV PRESS, 2018-05-04)Histone post-translational modifications (PTMs) generate a complex combinatorial code that regulates gene expression and nuclear functions, and whose deregulation has been documented in different types of cancers. Therefore, the availability of relevant culture models that can be manipulated and that retain the epigenetic features of the tissue of origin is absolutely crucial for studying the epigenetic mechanisms underlying cancer and testing epigenetic drugs. In this study, we took advantage of quantitative mass spectrometry to comprehensively profile histone PTMs in patient tumor tissues, primary cultures and cell lines from three representative tumor models, breast cancer, glioblastoma and ovarian cancer, revealing an extensive and systematic rewiring of histone marks in cell culture conditions, which includes a decrease of H3K27me2/me3, H3K79me1/me2 and H3K9ac/K14ac, and an increase of H3K36me1/me2. While some changes occur in short-term primary cultures, most of them are instead time-dependent and appear only in long-term cultures. Remarkably, such changes mostly revert in cell line- and primary cell-derived in vivo xenograft models. Taken together, these results support the use of xenografts as the most representative models of in vivo epigenetic processes, suggesting caution when using cultured cells, in particular cell lines and long-term primary cultures, for epigenetic investigations.Item IgG subclass switching and clonal expansion in cutaneous melanoma and normal skin.(NATURE PORTFOLIO, 2016-07-14)B cells participate in immune surveillance in human circulation and tissues, including tumors such as melanoma. By contrast, the role of humoral responses in cutaneous immunity is underappreciated. We report circulating skin-homing CD22+CLA+B cells in healthy volunteers and melanoma patients (n = 73) and CD22+ cells in melanoma and normal skin samples (n = 189). Normal and malignant skin featured mature IgG and CD22 mRNA, alongside mRNA for the transiently-expressed enzyme Activation-induced cytidine Deaminase (AID). Gene expression analyses of publically-available data (n = 234 GEO, n = 384 TCGA) confirmed heightened humoral responses (CD20, CD22, AID) in melanoma. Analyses of 51 melanoma-associated and 29 normal skin-derived IgG sequence repertoires revealed lower IgG1/IgGtotal representation compared with antibodies from circulating B cells. Consistent with AID, comparable somatic hypermutation frequencies and class-switching indicated affinity-matured antibodies in normal and malignant skin. A melanoma-associated antibody subset featured shorter complementarity-determining (CDR3) regions relative to those from circulating B cells. Clonal amplification in melanoma-associated antibodies and homology modeling indicated differential potential antigen recognition profiles between normal skin and melanoma sequences, suggesting distinct antibody repertoires. Evidence for IgG-expressing B cells, class switching and antibody maturation in normal and malignant skin and clonally-expanded antibodies in melanoma, support the involvement of mature B cells in cutaneous immunity.Item Single-cell transcriptomics reveals multi-step adaptations to endocrine therapy.(NATURE PORTFOLIO, 2019-09-02)Resistant tumours are thought to arise from the action of Darwinian selection on genetically heterogenous cancer cell populations. However, simple clonal selection is inadequate to describe the late relapses often characterising luminal breast cancers treated with endocrine therapy (ET), suggesting a more complex interplay between genetic and non-genetic factors. Here, we dissect the contributions of clonal genetic diversity and transcriptional plasticity during the early and late phases of ET at single-cell resolution. Using single-cell RNA-sequencing and imaging we disentangle the transcriptional variability of plastic cells and define a rare subpopulation of pre-adapted (PA) cells which undergoes further transcriptomic reprogramming and copy number changes to acquire full resistance. We find evidence for sub-clonal expression of a PA signature in primary tumours and for dominant expression in clustered circulating tumour cells. We propose a multi-step model for ET resistance development and advocate the use of stage-specific biomarkers.
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