Rosanna Upstill‐Goddard
A5023555185- Pancreatic and Hepatic Oncology Research
- Cancer Genomics and Diagnostics
- Phagocytosis and Immune Regulation
- Cancer Cells and Metastasis
- Proteoglycans and glycosaminoglycans research
- Epigenetics and DNA Methylation
- FOXO transcription factor regulation
- Fibroblast Growth Factor Research
- Genetic Associations and Epidemiology
- CAR-T cell therapy research
- Metastasis and carcinoma case studies
- RNA modifications and cancer
- Cancer Immunotherapy and Biomarkers
- Sarcoma Diagnosis and Treatment
- Immune Cell Function and Interaction
- Cancer Mechanisms and Therapy
- Neuroendocrine Tumor Research Advances
- Cleft Lip and Palate Research
- PI3K/AKT/mTOR signaling in cancer
- BRCA gene mutations in cancer
- Renal and related cancers
- Angiogenesis and VEGF in Cancer
- Genomic variations and chromosomal abnormalities
- Pancreatic function and diabetes
- Craniofacial Disorders and Treatments
University of Glasgow
2016-2025
Cancer Research UK Scotland Institute
2019-2023
University of Southampton
2012-2022
Switch
2019-2020
Southampton General Hospital
2014
University Hospital Southampton NHS Foundation Trust
2012
CXCR2 has been suggested to have both tumor-promoting and tumor-suppressive properties. Here we show that signaling is upregulated in human pancreatic cancer, predominantly neutrophil/myeloid-derived suppressor cells, but rarely tumor cells. Genetic ablation or inhibition of abrogated metastasis, only slowed tumorigenesis. Depletion neutrophils/myeloid-derived cells also suppressed metastasis suggesting a key role for establishing maintaining the metastatic niche. Importantly, loss improved...
Abstract MYC is implicated in the development and progression of pancreatic cancer, yet precise level deregulation required to contribute tumor has been difficult define. We used modestly elevated expression human MYC, driven from Rosa26 locus, investigate phenotypes arising mice an approximation trisomy. show that this alone suffices drive neuroendocrine tumors, accelerate KRAS-initiated precursor lesions metastatic ductal adenocarcinoma (PDAC). Our phenotype exposed suppression type I...
Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set become second leading cause of death in our society. The study aim was investigate association between DNA damage response (DDR), replication stress, and novel therapeutic PC develop a biomarker-driven strategy targeting DDR stress PC.
<h3>Background</h3> Multiple genes have been implicated by association studies in altering inflammatory bowel disease (IBD) predisposition. Paediatric patients often manifest more extensive and a particularly severe course. It is likely that genetic predisposition plays substantial role this group. <h3>Objective</h3> To identify the spectrum of rare novel variation known IBD susceptibility using exome sequencing analysis eight individual cases childhood onset disease. <h3>Design</h3> DNA...
Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these are driven by distinct metabolic phenotypes. Loss of genes drive endodermal lineage specification, HNF4A GATA6, switch profiles from predominantly squamous, glycogen synthase kinase 3 beta (GSK3β) a key regulator glycolysis. Pharmacological inhibition GSK3β results in selective sensitivity the squamous subtype;...
Abstract Background Pancreatic ductal adenocarcinoma (PDAC) remains a dismal disease, with very little improvement in survival over the past 50 years. Recent large-scale genomic studies have improved understanding of and transcriptomic landscape yet is known about molecular heterogeneity according to tumour location pancreas; body tail PDACs especially tend significantly worse prognosis. The aim was investigate differences between PDAC head those pancreas. Methods Detailed correlative...
Objective Immunotherapy for the treatment of pancreatic ductal adenocarcinoma (PDAC) has shown limited efficacy. Poor CD8 T-cell infiltration, low neoantigen load and a highly immunosuppressive tumour microenvironment contribute to this lack response. Here, we aimed further investigate immunoregulatory function focal adhesion kinase (FAK) in PDAC, with specific emphasis on regulation type-II interferon response that is critical promoting recognition effective immunosurveillance. Design We...
Missense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we present ten independent families with severe, progressive muscular dystrophy, reminiscent oculopharyngeal dystrophy (OPMD) but much earlier onset, caused by heterozygous frameshift the RBP hnRNPA2/B1. All disease-causing mutations abolish native stop codon extend reading frame, creating novel...
Abstract: Next-generation sequencing is enabling molecularly guided therapy for many cancer types, yet failure rates remain relatively high in pancreatic (PC). The aim of this study to investigate the feasibility genomic profiling using endoscopic ultrasound (EUS) biopsy samples facilitate personalised PC. Ninty-five patients underwent additional research biopsies at time diagnostic EUS. Diagnostic formalin-fixed (FFPE) and fresh frozen EUS DNA extraction, quantification targeted gene...
Objective Cytotoxic agents are the cornerstone of treatment for patients with advanced intrahepatic cholangiocarcinoma (iCCA), despite heterogeneous benefit. We hypothesised that pretreatment molecular profiles diagnostic biopsies can predict patient benefit from chemotherapy and define bases innate chemoresistance. Design identified a cohort iCCA comparable baseline characteristics who diverged as extreme outliers on (survival <6 m in rapid progressors, RP; survival >23 long...
<p>Release from AZD6244 treatment results in rapid acinar to ductal metaplasia KC KrasG12D/fl.</p>
<p>Early intervention with AZD6244 reduces PanIN burden in <i>Kras</i><sup>G12D/fl</sup> mice. <b>A,</b> Experimental schematic. KC were treated from day 42 for 28 days vehicle or and sampled at 70. <b>B,</b> Representative hematoxylin eosin (H&E), pERK1/2, Ki67 IHC images pancreata of mice 70 age following treatment as indicated days. four per group. Scale bar, 200 μm. <b>C,</b> Quantification grading PanINs...
<p>Increased fibrosis in wild-type Kras deficient PanINs.</p>
<p>Loss of wild-type KRAS sensitizes KPC KrasG12D/fl tumours to MEK1/2 inhibition.</p>
<div>Abstract<p>Pancreatic cancer is characterized by the prevalence of oncogenic mutations in <i>KRAS</i>. Previous studies have reported that altered <i>KRAS</i> gene dosage drives progression and metastasis pancreatic cancer. Whereas role well characterized, relevance partnering wild-type (WT) allele less understood controversial. Using <i>in vivo</i> mouse modeling cancer, we demonstrated WT KRAS restrains impact mutant dramatically impacts...
<p>Loss of WT <i>Kras</i> increases PanIN formation in the presence oncogenic <i>Kras</i>. <b>A,</b> Kaplan–Meier survival curve for human patients with PDAC <i>KRAS</i> alleles balanced and imbalanced. KRAS balanced, <i>n</i> = 47; imbalanced, 32. *, <i>P</i> 0.029, log-rank (Mantel–Cox) test. <b>B,</b> Proportion pancreatic cancer (59.5%) imbalanced (40.5%), from <b>A</b>....
<p>Acceleration of pancreatic tumour initiation after loss wild-type Kras in KPC KrasG12D/fl mice.</p>
<p>Late-stage intervention with MEK1/2 inhibition improves survival of KPC <i>Kras</i><sup>G12D/fl</sup> mice. <b>A,</b> Experimental schematic. <i>Kras</i><sup>G12D/+</sup> and mice were palpated for tumor burden, palpable burden confirmed by ultrasound imaging, treated continuously from the following day either vehicle or AZD6244. Tumor growth was monitored imaging once weekly to clinical endpoint. <b>B,</b>...
<p>Loss of WT KRAS induces increased MAPK signaling in KPC <i>Kras</i><sup>G12D/fl</sup>. <b>A,</b> Experimental schematic representing mice imaged once weekly by ultrasound from 6 weeks age to clinical endpoint follow tumor growth over time. <b>B,</b> Tumor volume relative that at initial detection <i>Kras</i><sup>G12D/+</sup> and <i>Kras</i><sup>G12D/fl</sup> aged measured imaging age....
<p>Loss of wild-type KRAS does not alter PI3K-AKT signalling.</p>
<p>MEK1/2 inhibition in KPC KrasG12D/fl mice with established tumours reverses enrichment of immune response related gene programmes.</p>
In pancreatic ductal adenocarcinoma cancer (PDAC) drug resistance is a severe clinical problem and patients relapse within few months after receiving the standard-of-care chemotherapy. One contributing factor to treatment desmoplastic nature of PDAC; tumours are surrounded by thick layers stroma composing up 90% tumour mass. This stroma, which mostly comprised extracellular matrix (ECM) proteins, secreted cancer-associated fibroblasts (CAFs) residing in microenvironment. However, mechanistic...