Search

Your search keyword '"Arafath K, Najumudeen"' showing total 3 results
Start Over Author "Arafath K, Najumudeen" Topic colorectal cancer
3 results on '"Arafath K, Najumudeen"'

1. Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition

Author

Amy K. Holt, Arafath K. Najumudeen, Tracey J. Collard, Hao Li, Laura M. Millett, Ashley J. Hoskin, Danny N. Legge, Eleanor M. H. Mortensson, Dustin J. Flanagan, Nicholas Jones, Madhu Kollareddy, Penny Timms, Matthew D. Hitchings, James Cronin, Owen J. Sansom, Ann C. Williams, and Emma E. Vincent

Subjects
Colorectal cancer, Aspirin, Metabolism, Metabolic reprogramming, CB-839, Glutaminase, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background To support proliferation and survival within a challenging microenvironment, cancer cells must reprogramme their metabolism. As such, targeting cancer cell metabolism is a promising therapeutic avenue. However, identifying tractable nodes of metabolic vulnerability in cancer cells is challenging due to their metabolic plasticity. Identification of effective treatment combinations to counter this is an active area of research. Aspirin has a well-established role in cancer prevention, particularly in colorectal cancer (CRC), although the mechanisms are not fully understood. Methods We generated a model to investigate the impact of long-term (52 weeks) aspirin exposure on CRC cells, which has allowed us comprehensively characterise the metabolic impact of long-term aspirin exposure (2–4mM for 52 weeks) using proteomics, Seahorse Extracellular Flux Analysis and Stable Isotope Labelling (SIL). Using this information, we were able to identify nodes of metabolic vulnerability for further targeting, investigating the impact of combining aspirin with metabolic inhibitors in vitro and in vivo. Results We show that aspirin regulates several enzymes and transporters of central carbon metabolism and results in a reduction in glutaminolysis and a concomitant increase in glucose metabolism, demonstrating reprogramming of nutrient utilisation. We show that aspirin causes likely compensatory changes that render the cells sensitive to the glutaminase 1 (GLS1) inhibitor—CB-839. Of note given the clinical interest, treatment with CB-839 alone had little effect on CRC cell growth or survival. However, in combination with aspirin, CB-839 inhibited CRC cell proliferation and induced apoptosis in vitro and, importantly, reduced crypt proliferation in Apc fl/fl mice in vivo. Conclusions Together, these results show that aspirin leads to significant metabolic reprogramming in colorectal cancer cells and raises the possibility that aspirin could significantly increase the efficacy of metabolic cancer therapies in CRC.

Published
2023
Full Text
View/download PDF

2. Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia

Author

Ester Gil Vazquez, Nadia Nasreddin, Gabriel N. Valbuena, Eoghan J. Mulholland, Hayley L. Belnoue-Davis, Holly R. Eggington, Ryan O. Schenck, Valérie M. Wouters, Pratyaksha Wirapati, Kathryn Gilroy, Tamsin R.M. Lannagan, Dustin J. Flanagan, Arafath K. Najumudeen, Sulochana Omwenga, Amy M.B. McCorry, Alistair Easton, Viktor H. Koelzer, James E. East, Dion Morton, Livio Trusolino, Timothy Maughan, Andrew D. Campbell, Maurice B. Loughrey, Philip D. Dunne, Petros Tsantoulis, David J. Huels, Sabine Tejpar, Owen J. Sansom, Simon J. Leedham, Center of Experimental and Molecular Medicine, and CCA - Cancer biology and immunology

Subjects
EXPRESSION, colorectal cancer, Receptors, G-Protein-Coupled, Mice, G-Protein-Coupled, intestinal polyps, SDG 3 - Good Health and Well-being, Cell & Tissue Engineering, stem cells, COLON, cell plasticity, colorectal neoplasia, intestinal stem cells, molecular phenotyping, Animals, Homeostasis, Humans, Intestines, Neoplastic Stem Cells, Colorectal Neoplasms, Intestinal Mucosa, Receptors, TUMORIGENESIS, PROGRAM, Genetics, PLASTICITY, SIGNATURES, SMALL-INTESTINE, Science & Technology, IDENTIFICATION, IN-VITRO, Cell Biology, METASTASIS, Molecular Medicine, Life Sciences & Biomedicine
Abstract

Intestinal homeostasis is underpinned by LGR5+ve crypt-base columnar stem cells (CBCs), but following injury, dedifferentiation results in the emergence of LGR5-ve regenerative stem cell populations (RSCs), characterized by fetal transcriptional profiles. Neoplasia hijacks regenerative signaling, so we assessed the distribution of CBCs and RSCs in mouse and human intestinal tumors. Using combined molecular-morphological analysis, we demonstrate variable expression of stem cell markers across a range of lesions. The degree of CBC-RSC admixture was associated with both epithelial mutation and microenvironmental signaling disruption and could be mapped across disease molecular subtypes. The CBC-RSC equilibrium was adaptive, with a dynamic response to acute selective pressure, and adaptability was associated with chemoresistance. We propose a fitness landscape model where individual tumors have equilibrated stem cell population distributions along a CBC-RSC phenotypic axis. Cellular plasticity is represented by position shift along this axis and is influenced by cell-intrinsic, extrinsic, and therapeutic selective pressures. ispartof: CELL STEM CELL vol:29 issue:8 pages:1213-+ ispartof: location:United States status: published

Published
2022

3. Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis

Author

Joshua D. G. Leach, Nikola Vlahov, Petros Tsantoulis, Rachel A. Ridgway, Dustin J. Flanagan, Kathryn Gilroy, Nathalie Sphyris, Ester G. Vázquez, David F. Vincent, William J. Faller, Michael C. Hodder, Alexander Raven, Sigrid Fey, Arafath K. Najumudeen, Douglas Strathdee, Colin Nixon, Mark Hughes, William Clark, Robin Shaw, S:CORT consortium, Sander R. van Hooff, David J. Huels, Jan Paul Medema, Simon T. Barry, Margaret C. Frame, Asier Unciti-Broceta, Simon J. Leedham, Gareth J. Inman, Rene Jackstadt, Barry J. Thompson, Andrew D. Campbell, Sabine Tejpar, Owen J. Sansom, Center of Experimental and Molecular Medicine, CCA - Cancer biology and immunology, and Radiotherapy

Subjects
0301 basic medicine, Chemistry(all), MICROSATELLITE INSTABILITY, Carcinogenesis, Colorectal cancer, Cellular differentiation, Receptor, Transforming Growth Factor-beta Type I, General Physics and Astronomy, SESSILE SERRATED ADENOMAS, DISTAL COLON, Kaplan-Meier Estimate, medicine.disease_cause, COLORECTAL-CANCER, 0302 clinical medicine, Transforming Growth Factor beta, Wnt Signaling Pathway, IN-VIVO, Mutation, Multidisciplinary, Cancer stem cells, Wnt signaling pathway, LGR5, Cell Differentiation, Prognosis, Multidisciplinary Sciences, 030220 oncology & carcinogenesis, Colonic Neoplasms, Science & Technology - Other Topics, Stem cell, STEM-CELLS, Signal Transduction, EXPRESSION, Proto-Oncogene Proteins B-raf, Cell Survival, Colon, MAP Kinase Signaling System, Science, INHIBITION, Physics and Astronomy(all), Biology, Article, General Biochemistry, Genetics and Molecular Biology, WNT ACTIVATION, 03 medical and health sciences, Fetus, SDG 3 - Good Health and Well-being, Spheroids, Cellular, medicine, Animals, Progenitor cell, Cancer models, Adaptor Proteins, Signal Transducing, Inflammation, Science & Technology, Biochemistry, Genetics and Molecular Biology(all), INTESTINAL REGENERATION, Epithelial Cells, YAP-Signaling Proteins, General Chemistry, medicine.disease, digestive system diseases, Mice, Inbred C57BL, Wnt Proteins, 030104 developmental biology, Cancer research, Receptors, Transforming Growth Factor beta, Transcription Factors
Abstract

Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFβ signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFβ-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype (Ly6a/Sca1+) and, importantly, lack expression of Lgr5 and its associated intestinal stem cell signature. These features are recapitulated in human BRAF-mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. Microbial-driven inflammation supports the initiation and progression of these tumours with foetal-like characteristics, consistent with their predilection for the microbe-rich right colon and their antibiotic sensitivity. While MAPK-pathway activating mutations drive this foetal-like signature via ERK-dependent activation of the transcriptional coactivator YAP, the same foetal-like transcriptional programs are also initiated by inflammation in a MAPK-independent manner. Importantly, in both contexts, epithelial TGFβ-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells., Right-sided colorectal cancer (rCRC) has a different mutational spectrum to the left-sided counterpart. Here the authors develop a mouse model of rCRC that recapitulates human BRAF-mutant rCRC and show that loss of TGFβ-receptor signalling and inflammation induce the development of colonic tumours with a foetal-like phenotype.

Published
2021

Catalog

Books, media, physical & digital resources
See catalog results