A5086450710- Cancer Cells and Metastasis
- Cancer-related Molecular Pathways
- Cancer and Skin Lesions
- Cancer Genomics and Diagnostics
- Molecular Biology Techniques and Applications
- Epigenetics and DNA Methylation
- Pancreatic and Hepatic Oncology Research
- Urologic and reproductive health conditions
- Pregnancy and preeclampsia studies
- Immune Cell Function and Interaction
- Single-cell and spatial transcriptomics
- Sexual Differentiation and Disorders
- Reproductive System and Pregnancy
- DNA Repair Mechanisms
- Cancer-related gene regulation
- T-cell and B-cell Immunology
- Esophageal Cancer Research and Treatment
- Genetic factors in colorectal cancer
- Skin and Cellular Biology Research
- Ubiquitin and proteasome pathways
- Advanced biosensing and bioanalysis techniques
- Acute Lymphoblastic Leukemia research
- RNA modifications and cancer
- Carcinogens and Genotoxicity Assessment
- NF-κB Signaling Pathways
The Gurdon Institute
2023-2024
University of Cambridge
2023-2024
Wellcome Sanger Institute
2019-2024
Fundacion Agencia Aragonesa para la Investigacion y el Desarrollo
2024
Instituto de Investigación Sanitaria Aragón
2024
Wellcome Trust
2023
Universidad Europea
2021
Centro Nacional de Biotecnología
2011-2018
Consejo Superior de Investigaciones Científicas
2011-2013
As humans age, normal tissues, such as the esophageal epithelium, become a patchwork of mutant clones. Some mutations are under positive selection, conferring competitive advantage over wild-type cells. We speculated that altering selective pressure on cell populations may cause them to expand or contract. tested this hypothesis by examining effect oxidative stress from low-dose ionizing radiation (LDIR) and p53 cells in transgenic mouse esophagus. found LDIR drives stop proliferating...
Abstract Skin cancer risk varies substantially across the body, yet how this relates to mutations found in normal skin is unknown. Here we mapped mutant clones from high- and low-risk sites. The density of varied by location. prevalence NOTCH1 FAT1 forearm, trunk, leg was similar that keratinocyte cancers. Most were caused ultraviolet light, but mutational signature analysis suggested differences DNA-repair processes between Eleven genes under positive selection, with TP53 preferentially...
Abstract In adult skin epidermis and the epithelium lining esophagus cells are constantly shed from tissue surface replaced by cell division. Tracking genetically labelled in transgenic mice has given insight into behavior, but conflicting models appear consistent with results. Here, we use an additional assay to follow division mouse at multiple body sites. We find that proliferating divide a similar rate, place bounds on distribution cycle times. By including these results common analytic...
Abstract Aging normal human oesophagus accumulates TP53 mutant clones. These are the origin of most oesophageal squamous carcinomas, in which biallelic disruption is almost universal. However, how p53 clones expand and contribute to cancer development unclear. Here we show that inducing R245W single progenitor cells transgenic mice confers a proliferative advantage clonal expansion but does not disrupt epithelial structure. Loss remaining allele results genomically unstable R245W/null...
The placenta is a selective maternal-fetal barrier that provides nourishment and protection from infections. However, certain pathogens can attach to even cross the placenta, causing pregnancy complications with potential lifelong impacts on child's health. Here, we profiled at single-cell level placental responses three associated intrauterine complications—Plasmodium falciparum, Listeria monocytogenes, Toxoplasma gondii. We found upon exposure pathogens, all lineages trigger inflammatory...
Oncogenic PIK3CA mutations generate large clones in aging human esophagus. Here we investigate the behavior of Pik3ca mutant normal esophageal epithelium transgenic mice. Expression a heterozygous
Abstract A novel suspension multiplex immunoassay for the simultaneous specific detection of lung cancer markers in bronchoalveolar lavage fluid (BALF) clinical samples based on fluorescent microspheres having different size and spectrally encoded with quantum dots (QDEM) was developed. The designed validated quantitative three BALF from 42 patients 10 control subjects. Tumor were detected through formation immune complexes consisting a capture molecule, target antigen, biotinylated...
c-Myc, a member of the Myc family transcription factors, is involved in numerous biological functions including regulation cell proliferation, differentiation, and apoptosis various types. Of all its functions, role c-Myc differentiation one least understood. We addressed B lymphocyte differentiation. found that essential from early stages vivo regulates this process by providing identity via direct transcriptional ebf-1 gene. Our data show influences promoting activation genes, thus linking...
The immune response involves the generation of Ab-secreting cells and memory B through a process called terminal lymphocyte differentiation. This program requires transcriptional repressor Blimp-1, which inhibits c-myc expression terminates proliferation. Although role c-Myc in cell proliferation is well characterized, it not known whether has other functions In this study, we show that only regulates proliferation, but also essential for function differentiation vivo. c-Myc-deficient...
Summary Normal human tissues progressively accumulate cells carrying mutations. Activating mutations in PIK3CA generate large clones the aging esophagus, but underlying cellular mechanisms are unclear. Here, we tracked mutant esophageal progenitor transgenic mice by lineage tracing. Expression of an activating heterozygous Pik3ca H1047R mutation single tilts cell fate towards proliferation, generating that outcompete their wild type neighbors. The leads to increased aerobic glycolysis...
ABSTRACT Studying long-term biological processes such as the colonization of aging epithelia by somatic mutant clones has been slowed lack suitable culture systems. Here we describe epithelioids, a facile, cost-effective method culturing multiple mouse and human epithelia. Esophageal epithelioids self-maintain without passaging for at least year, recapitulating 3D structure, cell dynamics, transcriptome, genomic stability esophagus. Live imaging over 5 months showed replicate in vivo...
The global compaction state of chromatin in a nucleus is an important component cell identity that has been difficult to measure. We have developed quantitative method measure the both live and fixed cells, without need for genetic modification, using fluorescence lifetime SiR-DNA dye. After optimising this cancer lines treated induce or decompaction, we observed differentiating epithelial cells tissue sections, as well local decompaction foci may represent transcription factories. In...
Abstract Adult tissues such as the epidermis of skin and epithelium lining esophagus are continuously turned over throughout life. Cells shed from tissue surface replaced by cell division. Yet, cellular mechanisms that underpin these homeostasis remain poorly established, having important implications for wound healing carcinogenesis. Lineage tracing, in which a cohort proliferating cells their descendants genetically labelled transgenic mice, has been used to study fate behavior maintain...
Summary Human epithelial tissues accumulate cancer-driver mutations with age 1–7 , yet tumor formation remains rare. The positive selection of these argues they alter the behavior and fitness proliferating cells 8–10 . Hence, normal adult become a patchwork mutant clones competing for space survival, fittest expanding by eliminating their less-competitive neighbors 9–12 However, little is known about how such dynamic competition in epithelia impacts early tumorigenesis. Here we show that...
Background: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer with a cumulative risk of ∼1 in 2,000 children by age 15 years and an increasing incidence over last 30 years.Activating mutations NOTCH1 gene are found more than 60% cases T‐cell Lymphoblastic leukaemia (T‐ALL) being targeted therapeutically compounds such as γ‐secretase inhibitors (GSIs) Notch inhibiting antibodies (mAbs). Aims: To identify novel therapeutic vulnerabilities Notch1 driven T‐ALL. Methods: A...
Abstract Placental infections are a major worldwide burden, particularly in developing countries. The placenta is transient tissue located at the interface between mother and fetus. Some pathogens can access placental barrier resulting pathological transmission from to fetus, which may have profound impact on health of Limited accessibility, critical differences humans mice, and, until recently, lack proper vitro models, hampered our understanding early response pathogens. Here we use...
<p>Supplementary Figures S1-S7 and Tables S1 S2</p>
<p>Supplementary Tables S3 to S8</p>
<div>Abstract<p>Skin cancer risk varies substantially across the body, yet how this relates to mutations found in normal skin is unknown. Here we mapped mutant clones from high- and low-risk sites. The density of varied by location. prevalence <i>NOTCH1</i> <i>FAT1</i> forearm, trunk, leg was similar that keratinocyte cancers. Most were caused ultraviolet light, but mutational signature analysis suggested differences DNA-repair processes between Eleven...
<p>Supplementary Tables S3 to S8</p>