Cancer Biology
https://repository.icr.ac.uk/handle/internal/3
2024-03-29T15:38:16ZOn the Co-Dependence of Cell Morphology and Biochemistry in Cancer
https://repository.icr.ac.uk/handle/internal/6192
On the Co-Dependence of Cell Morphology and Biochemistry in Cancer
Jones, I
Bakal, C
Shape and form are fundamental to biology. Acting at all scales, from the organismal to the molecular, morphology defines the functionality of biological structures. It is obvious that chemical events in the cell, influence cell morphology; we need look no further than the regulation of the cytoskeleton. However, it is becoming clear that this relationship goes both ways; while cellular biochemistry can control cell shape, so to can shape colour cellular chemistries. An excellent example of this phenomenon can be found in cell size. It is known that several cell types harbour ’size-control’ mechanisms, such to ensure that they do not deviate from a set size range when growing and dividing. The existence of such systems implies an ’optimal size’ for a given cell type, with the scale of a cell having far reaching consequences for its biochemistry. Strikingly, it has been observed that not only does the whole cell dilute as it enlarges but that different proteins do so at different rates. Thus, the balance of proteins in a cell, is directly influenced by cell growth and morphology. The relationship between cell chemistry and shape is not one-way, but rather a loop. As cell morphology depends on intracellular processes, and intracelluar processes on cell morphology, to study either in isolation can never provide a full picture. Studies must integrate data across modalities to capture cryptic inter-dependencies. Such studies are not trivial to perform and require the construction and analysis of vast data-sets, often comprised of source data generated by very different methods, each requiring individual treatment and assessment prior to integration with other sources. This complexity necessitates the application of modern computational methods to extract meaningful conclusions from data at this scale. Here, I demonstrate the power of these approaches in understanding the rich reciprocity of form and function.
2024-03-25T00:00:00ZDNA-PKcs is required for cGAS/STING-dependent viral DNA sensing in human cells.
https://repository.icr.ac.uk/handle/internal/6187
DNA-PKcs is required for cGAS/STING-dependent viral DNA sensing in human cells.
Hristova, DB; Oliveira, M; Wagner, E; Melcher, A; Harrington, KJ; Belot, A; Ferguson, BJ
To mount an efficient interferon response to virus infection, intracellular pattern recognition receptors (PRRs) sense viral nucleic acids and activate anti-viral gene transcription. The mechanisms by which intracellular DNA and DNA viruses are sensed are relevant not only to anti-viral innate immunity, but also to autoinflammation and anti-tumour immunity through the initiation of sterile inflammation by self-DNA recognition. The PRRs that directly sense and respond to viral or damaged self-DNA function by signaling to activate interferon regulatory factor (IRF)-dependent type one interferon (IFN-I) transcription. We and others have previously defined DNA-dependent protein kinase (DNA-PK) as an essential component of the DNA-dependent anti-viral innate immune system. Here, we show that DNA-PK is essential for cyclic GMP-AMP synthase (cGAS)- and stimulator of interferon genes (STING)-dependent IFN-I responses in human cells during stimulation with exogenous DNA and infection with DNA viruses.
2024-01-19T00:00:00ZThe role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance.
https://repository.icr.ac.uk/handle/internal/6165
The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance.
Caswell, DR; Gui, P; Mayekar, MK; Law, EK; Pich, O; Bailey, C; Boumelha, J; Kerr, DL; Blakely, CM; Manabe, T; Martinez-Ruiz, C; Bakker, B; De Dios Palomino Villcas, J; I Vokes, N; Dietzen, M; Angelova, M; Gini, B; Tamaki, W; Allegakoen, P; Wu, W; Humpton, TJ; Hill, W; Tomaschko, M; Lu, W-T; Haderk, F; Al Bakir, M; Nagano, A; Gimeno-Valiente, F; de Carné Trécesson, S; Vendramin, R; Barbè, V; Mugabo, M; Weeden, CE; Rowan, A; McCoach, CE; Almeida, B; Green, M; Gomez, C; Nanjo, S; Barbosa, D; Moore, C; Przewrocka, J; Black, JRM; Grönroos, E; Suarez-Bonnet, A; Priestnall, SL; Zverev, C; Lighterness, S; Cormack, J; Olivas, V; Cech, L; Andrews, T; Rule, B; Jiao, Y; Zhang, X; Ashford, P; Durfee, C; Venkatesan, S; Temiz, NA; Tan, L; Larson, LK; Argyris, PP; Brown, WL; Yu, EA; Rotow, JK; Guha, U; Roper, N; Yu, J; Vogel, RI; Thomas, NJ; Marra, A; Selenica, P; Yu, H; Bakhoum, SF; Chew, SK; Reis-Filho, JS; Jamal-Hanjani, M; Vousden, KH; McGranahan, N; Van Allen, EM; Kanu, N; Harris, RS; Downward, J; Bivona, TG; Swanton, C
In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.
2024-01-01T00:00:00ZVitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer.
https://repository.icr.ac.uk/handle/internal/6138
Vitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer.
Kreuzaler, P; Inglese, P; Ghanate, A; Gjelaj, E; Wu, V; Panina, Y; Mendez-Lucas, A; MacLachlan, C; Patani, N; Hubert, CB; Huang, H; Greenidge, G; Rueda, OM; Taylor, AJ; Karali, E; Kazanc, E; Spicer, A; Dexter, A; Lin, W; Thompson, D; Silva Dos Santos, M; Calvani, E; Legrave, N; Ellis, JK; Greenwood, W; Green, M; Nye, E; Still, E; CRUK Rosetta Grand Challenge Consortium; Barry, S; Goodwin, RJA; Bruna, A; Caldas, C; MacRae, J; de Carvalho, LPS; Poulogiannis, G; McMahon, G; Takats, Z; Bunch, J; Yuneva, M
Tumors are intrinsically heterogeneous and it is well established that this directs their evolution, hinders their classification and frustrates therapy1-3. Consequently, spatially resolved omics-level analyses are gaining traction4-9. Despite considerable therapeutic interest, tumor metabolism has been lagging behind this development and there is a paucity of data regarding its spatial organization. To address this shortcoming, we set out to study the local metabolic effects of the oncogene c-MYC, a pleiotropic transcription factor that accumulates with tumor progression and influences metabolism10,11. Through correlative mass spectrometry imaging, we show that pantothenic acid (vitamin B5) associates with MYC-high areas within both human and murine mammary tumors, where its conversion to coenzyme A fuels Krebs cycle activity. Mechanistically, we show that this is accomplished by MYC-mediated upregulation of its multivitamin transporter SLC5A6. Notably, we show that SLC5A6 over-expression alone can induce increased cell growth and a shift toward biosynthesis, whereas conversely, dietary restriction of pantothenic acid leads to a reversal of many MYC-mediated metabolic changes and results in hampered tumor growth. Our work thus establishes the availability of vitamins and cofactors as a potential bottleneck in tumor progression, which can be exploited therapeutically. Overall, we show that a spatial understanding of local metabolism facilitates the identification of clinically relevant, tractable metabolic targets.
2023-11-01T00:00:00Z