Browsing Cancer Biology by author "Downward, Julian David Harry"
Now showing items 1-20 of 28
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An Immunogenic Model of KRAS-Mutant Lung Cancer Enables Evaluation of Targeted Therapy and Immunotherapy Combinations.
Boumelha, J; de Carné Trécesson, S; Law, EK; Romero-Clavijo, P; Coelho, MA; et al. (AMER ASSOC CANCER RESEARCH, 2022-10-04)UNLABELLED: Mutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins cause tumor regression but ultimately fail to elicit cures. As a result, there is an intense ... -
Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells.
Wang, Y; Xiong, H; Liu, D; Hill, C; Ertay, A; et al. (2019-05)Macroautophagy/autophagy inhibition is a novel anticancer therapeutic strategy, especially for tumors driven by mutant RAS. Here, we demonstrate that autophagy inhibition in RAS-mutated cells induces epithelial-mesenchymal ... -
Autophagy inhibition-mediated epithelial-mesenchymal transition augments local myofibroblast differentiation in pulmonary fibrosis.
Hill, C; Li, J; Liu, D; Conforti, F; Brereton, CJ; et al. (2019-08-07)Idiopathic pulmonary fibrosis (IPF), the prototypic progressive fibrotic interstitial lung disease, is thought to be a consequence of repetitive micro-injuries to an ageing, susceptible alveolar epithelium. Ageing is a ... -
Bidirectional epithelial-mesenchymal crosstalk provides self-sustaining profibrotic signals in pulmonary fibrosis.
Yao, L; Zhou, Y; Li, J; Wickens, L; Conforti, F; et al. (ELSEVIER, 2021-09-01)Idiopathic pulmonary fibrosis (IPF) is the prototypic progressive fibrotic lung disease with a median survival of 2 to 4 years. Injury to and/or dysfunction of the alveolar epithelium is strongly implicated in IPF disease ... -
Characterisation of tumour microenvironment remodelling following oncogene inhibition in preclinical studies with imaging mass cytometry.
van Maldegem, F; Valand, K; Cole, M; Patel, H; Angelova, M; et al. (NATURE PORTFOLIO, 2021-10-08)Mouse models are critical in pre-clinical studies of cancer therapy, allowing dissection of mechanisms through chemical and genetic manipulations that are not feasible in the clinical setting. In studies of the tumour ... -
Clinical impact of subclonal EGFR T790M mutations in advanced-stage EGFR-mutant non-small-cell lung cancers.
Vaclova, T; Grazini, U; Ward, L; O'Neill, D; Markovets, A; et al. (2021-03-19)Advanced non-small-cell lung cancer (NSCLC) patients with EGFR T790M-positive tumours benefit from osimertinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). Here we show that the size of the ... -
Combined targeting of G protein-coupled receptor and EGF receptor signaling overcomes resistance to PI3K pathway inhibitors in PTEN-null triple negative breast cancer.
Zecchin, D; Moore, C; Michailidis, F; Horswell, S; Rana, S; et al. (2020-08)Triple-negative breast cancer (TNBC) has poorer prognosis compared to other types of breast cancers due to the lack of effective therapies and markers for patient stratification. Loss of PTEN tumor suppressor gene expression ... -
Concomitant KRAS mutations attenuate sensitivity of non-small cell lung cancer cells to KRAS G12C inhibition.
Vaclova, T; Chakraborty, A; Sherwood, J; Ross, S; Carroll, D; et al. (NATURE PORTFOLIO, 2022-02-17)The development of covalent inhibitors against KRAS G12C represents a major milestone in treatment of RAS-driven cancers, especially in non-small cell lung cancer (NSCLC), where KRAS G12C is one of the most common oncogenic ... -
Decreased glutathione biosynthesis contributes to EGFR T790M-driven erlotinib resistance in non-small cell lung cancer.
Li, H; Stokes, W; Chater, E; Roy, R; de Bruin, E; et al. (2016-01)Epidermal growth factor receptor (EGFR) inhibitors such as erlotinib are novel effective agents in the treatment of EGFR-driven lung cancer, but their clinical impact is often impaired by acquired drug resistance through ... -
Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer.
Molina-Arcas, M; Moore, C; Rana, S; van Maldegem, F; Mugarza, E; et al. (2019-09)KRAS represents an excellent therapeutic target in lung cancer, the most commonly mutated form of which can now be blocked using KRAS-G12C mutant-specific inhibitory trial drugs. Lung adenocarcinoma cells harboring KRAS ... -
Disruption of the Interaction of RAS with PI 3-Kinase Induces Regression of EGFR-Mutant-Driven Lung Cancer.
Murillo, MM; Rana, S; Spencer-Dene, B; Nye, E; Stamp, G; et al. (2018-12)RAS family GTPases contribute directly to the regulation of type I phosphoinositide 3-kinases (PI3Ks) via RAS-binding domains in the PI3K catalytic p110 subunits. Disruption of this domain of p110α impairs RAS-mutant-onc ... -
Facts and Hopes on RAS Inhibitors and Cancer Immunotherapy.
Boumelha, J; Molina-Arcas, M; Downward, J (AMER ASSOC CANCER RESEARCH, 2023-12-15)Although the past decade has seen great strides in the development of immunotherapies that reactivate the immune system against tumors, there have also been major advances in the discovery of drugs blocking oncogenic drivers ... -
IGF1-mediated human embryonic stem cell self-renewal recapitulates the embryonic niche.
Wamaitha, SE; Grybel, KJ; Alanis-Lobato, G; Gerri, C; Ogushi, S; et al. (2020-02-07)Our understanding of the signalling pathways regulating early human development is limited, despite their fundamental biological importance. Here, we mine transcriptomics datasets to investigate signalling in the human ... -
Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype.
Polubothu, S; Zecchin, D; Al-Olabi, L; Lionarons, DA; Harland, M; et al. (2021-06-18)Purpose Much of the heredity of melanoma remains unexplained. We sought predisposing germline copy-number variants using a rare disease approach.Methods Whole-genome copy-number findings in patients with melanoma predisposition ... -
Oncogenic RAS Signaling Promotes Tumor Immunoresistance by Stabilizing PD-L1 mRNA.
Coelho, MA; de Carné Trécesson, S; Rana, S; Zecchin, D; Moore, C; et al. (2017-12-12)The immunosuppressive protein PD-L1 is upregulated in many cancers and contributes to evasion of the host immune system. The relative importance of the tumor microenvironment and cancer cell-intrinsic signaling in the ... -
Paracrine signalling during ZEB1-mediated epithelial-mesenchymal transition augments local myofibroblast differentiation in lung fibrosis.
Yao, L; Conforti, F; Hill, C; Bell, J; Drawater, L; et al. (2019-05)The contribution of epithelial-mesenchymal transition (EMT) to human lung fibrogenesis is controversial. Here we provide evidence that ZEB1-mediated EMT in human alveolar epithelial type II (ATII) cells contributes to the ... -
The Potency of a KRAS Silent Variant.
Molina-Arcas, M; Downward, J; Phimister EG (Massachusetts Medical Society, 2022-06-30) -
Quantitative Proteomic Analysis in Alveolar Type II Cells Reveals the Different Capacities of RAS and TGF-β to Induce Epithelial-Mesenchymal Transition.
Zhou, Y; Hill, C; Yao, L; Li, J; Hancock, D; et al. (FRONTIERS MEDIA SA, 2021-03-19)Alveolar type II (ATII) epithelial cells function as stem cells, contributing to alveolar renewal, repair and cancer. Therefore, they are a highly relevant model for studying a number of lung diseases, including acute ... -
RAC1P29S Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance.
Lionarons, DA; Hancock, DC; Rana, S; East, P; Moore, C; et al. (2019-07)RAC1 P29 is the third most commonly mutated codon in human cutaneous melanoma, after BRAF V600 and NRAS Q61. Here, we study the role of RAC1P29S in melanoma development and reveal that RAC1P29S activates PAK, AKT, and a ... -
RAS oncogenic activity predicts response to chemotherapy and outcome in lung adenocarcinoma.
East, P; Kelly, GP; Biswas, D; Marani, M; Hancock, DC; et al. (NATURE PORTFOLIO, 2022-09-26)Activating mutations in KRAS occur in 32% of lung adenocarcinomas (LUAD). Despite leading to aggressive disease and resistance to therapy in preclinical studies, the KRAS mutation does not predict patient outcome or response ...