A5034095842- Cancer Genomics and Diagnostics
- Immunotherapy and Immune Responses
- Immune cells in cancer
- PI3K/AKT/mTOR signaling in cancer
- Melanoma and MAPK Pathways
- Cancer Immunotherapy and Biomarkers
- RNA modifications and cancer
- Cutaneous Melanoma Detection and Management
- Digestive system and related health
- Immune responses and vaccinations
- Lung Cancer Treatments and Mutations
- Cancer Cells and Metastasis
- Cancer, Hypoxia, and Metabolism
- Peptidase Inhibition and Analysis
- Genetic factors in colorectal cancer
- Epigenetics and DNA Methylation
- Computational Drug Discovery Methods
- Immune Cell Function and Interaction
- Cancer-related Molecular Pathways
- Diet and metabolism studies
- Neuroendocrine Tumor Research Advances
- Ubiquitin and proteasome pathways
- Lung Cancer Research Studies
- Genetics and Neurodevelopmental Disorders
- Wnt/β-catenin signaling in development and cancer
The Francis Crick Institute
2016-2025
Cancer Research UK
2007-2023
CRUK Lung Cancer Centre of Excellence
2023
Royal United Hospital Bath NHS Trust
2023
Mary Lyon Centre at MRC Harwell
2020
Stem Cell Institute
2020
Office of the Assistant Secretary for Planning and Evaluation
2020
IFOM
2017
European Institute of Oncology
2017
ETH Zurich
2017
Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, polymorphic nature locus has precluded accurate HLA copy-number analysis. Here, we heterozygosity in (LOHHLA), computational tool determine allele-specific copy number from sequencing data. Using LOHHLA, find that LOH occurs 40% non-small-cell lung cancers (NSCLCs) and associated with high subclonal neoantigen burden,...
Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 biopsies across 100 patients with ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, identify 9p loss as highly selected event driving metastasis ccRCC-related mortality (p = 0.0014). Distinct patterns dissemination were observed, rapid progression multiple...
In mouse, a subset of dendritic cells (DCs) known as CD8α+ DCs has emerged an important player in the regulation T cell responses and promising target vaccination strategies. However, translation into clinical protocols been hampered by failure to identify humans. Here, we characterize population human that expresses DNGR-1 (CLEC9A) high levels BDCA3 resembles mouse phenotype function. We describe presence such spleens humans humanized mice report on protocol generate them vitro. Like DCs,...
The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. observe up 30 driver events per and show that subclonal diversification is associated with known prognostic parameters. By resolving patterns event ordering, co-occurrence, mutual exclusivity at clone level, we deterministic nature clonal evolution. ccRCC...
The Krebs cycle enzyme fumarate hydratase (FH) is a human tumor suppressor whose inactivation associated with the development of leiomyomata, renal cysts, and tumors. It has been proposed that activation hypoxia inducible factor (HIF) by fumarate-mediated inhibition HIF prolyl hydroxylases drives oncogenesis. Using mouse model, we provide genetic evidence Fh1-associated cyst formation Hif independent, as striking upregulation antioxidant signaling pathways revealed gene expression profiling....
The immunosuppressive protein PD-L1 is upregulated in many cancers and contributes to evasion of the host immune system. relative importance tumor microenvironment cancer cell-intrinsic signaling regulation expression remains unclear. We report that oncogenic RAS can upregulate cell through a mechanism involving increases mRNA stability via modulation AU-rich element-binding tristetraprolin (TTP). TTP negatively regulates elements 3′ UTR mRNA. MEK downstream leads phosphorylation inhibition...
CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that expression largely restricted to tumor-infiltrating Treg in mice humans. While existing were observed deplete the periphery, upregulation of inhibitory Fc gamma receptor (FcγR) IIb tumor site prevented intra-tumoral cell depletion, which may underlie lack...
The epithelium and immune compartment in the intestine are constantly exposed to a fluctuating external environment. Defective communication between these compartments at this barrier surface underlies susceptibility infections chronic inflammation. Environmental factors play significant, but mechanistically poorly understood, role intestinal homeostasis. We found that regeneration of epithelial cells (IECs) upon injury through infection or chemical insults was profoundly influenced by...
Tumors comprise functionally diverse subpopulations of cells with distinct proliferative potential. Here, we show that dynamic epigenetic states defined by the linker histone H1.0 determine which within a tumor can sustain long-term cancer growth. Numerous types exhibit high inter- and intratumor heterogeneity H1.0, levels correlating differentiation status, patient survival, and, at single-cell level, stem cell markers. Silencing promotes maintenance self-renewing inducing derepression...
Metastatic disease is responsible for the majority of cancer-related deaths
A role for vitamin D in immune modulation and cancer has been suggested. In this work, we report that mice with increased availability of display greater immune-dependent resistance to transplantable cancers augmented responses checkpoint blockade immunotherapies. Similarly, humans, D-induced genes correlate improved inhibitor treatment as well immunity overall survival. mice, is attributable the activity on intestinal epithelial cells, which alters microbiome composition favor
Abstract Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health 1 . This is compounded by the limited efficacy available treatments high failure during drug development 2 , highlighting an urgent need better understand mechanisms. Here we show how functional genomics could address this challenge. By investigating intergenic haplotype on chr21q22—which has been independently linked bowel disease, ankylosing spondylitis, primary sclerosing...
Abstract Understanding the role of tumor microenvironment (TME) in lung cancer is critical to improving patient outcomes. We identified four histology-independent archetype TMEs treatment-naïve early-stage using imaging mass cytometry TRACERx study (n = 81 patients/198 samples/2.3 million cells). In immune-hot adenocarcinomas, spatial niches T cells and macrophages increased with clonal neoantigen burden, whereas such an increase was observed for plasma B immune-excluded squamous cell...
Mucin-type O-glycans (O-glycans) are highly expressed in vascular ECs. However, it is not known whether they important for development. To investigate the roles of EC O-glycans, we generated mice lacking T-synthase, a glycosyltransferase encoded by gene C1galt1 that critical biosynthesis core 1-derived ECs and hematopoietic cells (termed here EHC T-syn(-/-) mice). exhibited embryonic neonatal lethality associated with disorganized blood-filled lymphatic vessels. Bone marrow transplantation...
Abstract Murine mesenchymal stem cells are capable of differentiation into multiple cell types both in vitro and vivo may be good candidates to use as therapy for diseased or damaged organs. We have previously reported a method enriching population murine MSCs that demonstrated diverse potential vivo. In this study, we show enriched embolize within lung capillaries following systemic injection then rapidly expand within, invade into, the parenchyma, forming tumor nodules. These lesions...
Highlights•Inducible disruption of PI3-kinase p110α interaction with RAS was modeled in mice•Blocking RAS/p110α established lung tumors causes partial regression•Blocking binding has effects similar to deletion on tumor regression•Coordinate MEK inhibition is required for major regression Kras mutant cancerSummaryRAS proteins directly activate PI3-kinases. Mice bearing a germline mutation the domain subunit PI3-kinse are resistant development RAS-driven tumors. However, it unknown whether...