39 results on '"Hanley CJ"'
Search Results
2. CD4+ follicular helper-like T cells are key players in anti-tumor immunity
- Author
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Singh, D, primary, Ganesan, AP, additional, Panwar, B, additional, Eschweiler, S, additional, Hanley, CJ, additional, Madrigal, A, additional, Ramírez-Suástegui, C, additional, Wang, A, additional, Clarke, J, additional, Wood, O, additional, Garrido-Martin, EM, additional, Chee, SJ, additional, Seumois, G, additional, Belanger, S, additional, Alzetani, A, additional, Woo, E, additional, Friedmann, PS, additional, Crotty, S, additional, Thomas, GJ, additional, Sanchez-Elsner, T, additional, Ay, F, additional, Ottensmeier, CH, additional, and Vijayanand, P, additional
- Published
- 2020
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3. Pro-migratory and TGF-β-activating functions of αvβ6 integrin in pancreatic cancer are differentially regulated via an Eps8-dependent GTPase switch
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Tod, J, Hanley, CJ, Morgan, MR, Rucka, M, Mellows, T, Lopez, M-A, Kiely, P, Moutasim, KA, Frampton, SJ, Sabnis, D, Fine, DR, Johnson, C, Marshall, JF, Scita, G, Jenei, V, and Thomas, GJ
- Abstract
The integrin αvβ6 is upregulated in numerous carcinomas, where expression commonly correlates with poor prognosis. αvβ6 promotes tumour invasion, partly through regulation of proteases and cell migration, and is also the principal mechanism by which epithelial cells activate TGF-β1; this latter function complicates therapeutic targeting of αvβ6, since TGF-β1 has both tumour-promoting and -suppressive effects. It is unclear how these different αvβ6 functions are linked; both require actin cytoskeletal reorganisation, and it is suggested that tractive forces generated during cell migration activate TGF-β1 by exerting mechanical tension on the ECM-bound latent complex. We examined the functional relationship between cell invasion and TGF-β1 activation in pancreatic ductal adenocarcinoma (PDAC) cells, and confirmed that both processes are αvβ6-dependent. Surprisingly, we found that cellular functions could be biased towards either motility or TGF-β1 activation depending on the presence or absence of epidermal growth factor receptor pathway substrate 8 (Eps8), a regulator of actin remodelling, endocytosis and GTPase activation. Similar to αvβ6, we found that Eps8 was upregulated in >70% of PDAC. In complex with Abi1/Sos1, Eps8 regulated αvβ6-dependent cell migration through activation of Rac1. Downregulation of Eps8, Sos1 or Rac1 suppressed cell movement, while simultaneously increasing αvβ6-dependent TGF-β1 activation. This latter effect was modulated through increased cell tension, regulated by Rho activation. Thus, the Eps8/Abi1/Sos1 tricomplex acts as a key molecular switch altering the balance between Rac1 and Rho activation; its presence or absence in PDAC cells modulates αvβ6-dependent functions, resulting in a pro-migratory (Rac1-dependent) or a pro-TGF-β1 activation (Rho-dependent) functional phenotype respectively.
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- 2017
4. Author Correction: mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype.
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Herranz N, Gallage S, Mellone M, Wuestefeld T, Klotz S, Hanley CJ, Raguz S, Acosta JC, Innes AJ, Banito A, Georgilis A, Montoya A, Wolter K, Dharmalingam G, Faull P, Carroll T, Martínez-Barbera JP, Cutillas P, Reisinger F, Heikenwalder M, Miller RA, Withers D, Zender L, Thomas GJ, and Gil J
- Published
- 2024
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5. The effects of age bias on neural correlates of successful and unsuccessful response inhibition in younger and older adults.
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Hanley CJ, Burns N, Thomas HR, Marstaller L, and Burianová H
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- Humans, Aged, Aging physiology, Magnetic Resonance Imaging, Inhibition, Psychological
- Abstract
Facilitating communication between generations has become increasingly important. However, individuals often demonstrate a preference for their own age group, which can impact social interactions, and such bias in young adults even extends to inhibitory control. To assess whether older adults also experience this phenomenon, a group of younger and older adults completed a Go/NoGo task incorporating young and old faces, while undergoing functional magnetic resonance imaging. Within the networks subserving successful and unsuccessful response inhibition, patterns of activity demonstrated distinct neural age bias effects in each age group. During successful inhibition, the older adult group demonstrated significantly increased activity to other-age faces, whereas unsuccessful inhibition in the younger group produced significantly enhanced activity to other-age faces. Consequently, the findings of the study confirm that neural responses to successful and unsuccessful inhibition can be contingent on the stimulus-specific attribute of age in both younger and older adults. These findings have important implications in regard to minimizing the emergence of negative consequences, such as ageism, as a result of related implicit biases., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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6. Improved understanding of NSCLC immunotherapy response mechanisms from single-cell analysis.
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Bienkowska KJ and Hanley CJ
- Abstract
Competing Interests: Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-428/coif). The authors have no conflicts of interest to declare.
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- 2023
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7. Single-cell analysis reveals prognostic fibroblast subpopulations linked to molecular and immunological subtypes of lung cancer.
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Hanley CJ, Waise S, Ellis MJ, Lopez MA, Pun WY, Taylor J, Parker R, Kimbley LM, Chee SJ, Shaw EC, West J, Alzetani A, Woo E, Ottensmeier CH, Rose-Zerilli MJJ, and Thomas GJ
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- Humans, Fibroblasts, Single-Cell Analysis, Lung Neoplasms genetics, Carcinoma, Non-Small-Cell Lung genetics, Adenocarcinoma of Lung genetics
- Abstract
Fibroblasts are poorly characterised cells that variably impact tumour progression. Here, we use single cell RNA-sequencing, multiplexed immunohistochemistry and digital cytometry (CIBERSORTx) to identify and characterise three major fibroblast subpopulations in human non-small cell lung cancer: adventitial, alveolar and myofibroblasts. Alveolar and adventitial fibroblasts (enriched in control tissue samples) localise to discrete spatial niches in histologically normal lung tissue and indicate improved overall survival rates when present in lung adenocarcinomas (LUAD). Trajectory inference identifies three phases of control tissue fibroblast activation, leading to myofibroblast enrichment in tumour samples: initial upregulation of inflammatory cytokines, followed by stress-response signalling and ultimately increased expression of fibrillar collagens. Myofibroblasts correlate with poor overall survival rates in LUAD, associated with loss of epithelial differentiation, TP53 mutations, proximal molecular subtypes and myeloid cell recruitment. In squamous carcinomas myofibroblasts were not prognostic despite being transcriptomically equivalent. These findings have important implications for developing fibroblast-targeting strategies for cancer therapy., (© 2023. The Author(s).)
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- 2023
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8. ATM Regulates Differentiation of Myofibroblastic Cancer-Associated Fibroblasts and Can Be Targeted to Overcome Immunotherapy Resistance.
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Mellone M, Piotrowska K, Venturi G, James L, Bzura A, Lopez MA, James S, Wang C, Ellis MJ, Hanley CJ, Buckingham JF, Cox KL, Hughes G, Valge-Archer V, King EV, Beers SA, Jaquet V, Jones GDD, Savelyeva N, Sayan E, Parsons JL, Durant S, and Thomas GJ
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- Humans, Cell Differentiation, Myofibroblasts metabolism, Drug Resistance, Neoplasm, Ataxia Telangiectasia Mutated Proteins metabolism, Cancer-Associated Fibroblasts metabolism, Immunotherapy, Neoplasms
- Abstract
Myofibroblastic cancer-associated fibroblast (myoCAF)-rich tumors generally contain few T cells and respond poorly to immune-checkpoint blockade. Although myoCAFs are associated with poor outcome in most solid tumors, the molecular mechanisms regulating myoCAF accumulation remain unclear, limiting the potential for therapeutic intervention. Here, we identify ataxia-telangiectasia mutated (ATM) as a central regulator of the myoCAF phenotype. Differentiating myofibroblasts in vitro and myoCAFs cultured ex vivo display activated ATM signaling, and targeting ATM genetically or pharmacologically could suppress and reverse differentiation. ATM activation was regulated by the reactive oxygen species-producing enzyme NOX4, both through DNA damage and increased oxidative stress. Targeting fibroblast ATM in vivo suppressed myoCAF-rich tumor growth, promoted intratumoral CD8 T-cell infiltration, and potentiated the response to anti-PD-1 blockade and antitumor vaccination. This work identifies a novel pathway regulating myoCAF differentiation and provides a rationale for using ATM inhibitors to overcome CAF-mediated immunotherapy resistance., Significance: ATM signaling supports the differentiation of myoCAFs to suppress T-cell infiltration and antitumor immunity, supporting the potential clinical use of ATM inhibitors in combination with checkpoint inhibition in myoCAF-rich, immune-cold tumors., (©2022 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2022
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9. Targeting cancer-associated fibroblasts: Challenges, opportunities and future directions.
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Jenkins BH, Buckingham JF, Hanley CJ, and Thomas GJ
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- Humans, Gene Expression Regulation, Neoplastic, Tumor Microenvironment genetics, Fibroblasts, Cancer-Associated Fibroblasts, Neoplasms drug therapy, Neoplasms genetics
- Abstract
Cancer-associated fibroblasts (CAFs) are a common cell in the tumour microenvironment with diverse tumour-promoting functions. Their presence in tumours is commonly associated with poor prognosis making them attractive therapeutic targets, particularly in the context of immunotherapy where CAFs have been shown to promote resistance to checkpoint blockade. Previous attempts to inhibit CAFs clinically have not been successful, however, in part due to a lack of understanding of CAF heterogeneity and function, with some fibroblast populations potentially being tumour suppressive. Recent single-cell transcriptomic studies have advanced our understanding of fibroblast phenotypes in normal tissues and cancers, allowing for a more precise characterisation of CAF subsets and providing opportunities to develop new therapies. Here we review recent advances in the field, focusing on the evolving area of therapeutic CAF targeting., Competing Interests: Declaration of Competing Interest C.J. Hanley and G.J. Thomas are co-inventors on patent WO2019086579 for the use of NOX inhibitors in cancer. B.H. Jenkins and J.F. Buckingham have no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2022
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10. The effects of age-bias on neural correlates of successful and unsuccessful response inhibition.
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Hanley CJ, Burns N, Thomas HR, Marstaller L, and Burianová H
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- Bias, Brain physiology, Humans, Magnetic Resonance Imaging methods, Young Adult, Brain Mapping methods, Inhibition, Psychological
- Abstract
Response inhibition is important for adherence to social norms, especially when norms conflict with biases based on one's social identity. While previous studies have shown that in-group bias generally modulates neural activity related to stimulus appraisal, it is unclear whether and how an in-group bias based on age affects neural information processing during response inhibition. To assess this potential influence, young adults completed a Go/NoGo task incorporating younger face (in-group) and older face (out-group) stimuli while undergoing functional magnetic resonance imaging (fMRI). Our results replicated previous findings by demonstrating higher accuracy in successful Go compared to NoGo trials, as well as the engagement of nodes of the response inhibition network during successful response inhibition, and brain regions comprising the salience network during unsuccessful response inhibition. Importantly, despite a lack of behavioural differences, our results showed that younger and older face stimuli modulated activity in the response inhibition and salience networks during successful and unsuccessful inhibition, respectively. Interestingly, these effects were not uniform across networks. During successful response inhibition, in-group stimuli increased activity in medial prefrontal cortex and temporo-parietal junction, whereas out-group stimuli more strongly engaged pre-supplemental motor area. During unsuccessful response inhibition, in-group stimuli increased activity in posterior insula, whereas out-group stimuli more strongly engaged angular gyrus and intraparietal sulcus. Consequently, the results infer the presence of an age-bias effect in the context of inhibitory control, which has substantial implications for future experimental design and may also provide the means of investigating the neural correlates of implicit beliefs that contribute to ageism., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2022
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11. Weaker connectivity in resting state networks is associated with disinhibited eating in older adults.
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Brennan A, Marstaller L, Burianová H, Benton D, Hanley CJ, Newstead S, and Young HA
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- Aged, Brain Mapping, Executive Function, Feeding Behavior, Humans, Obesity, Brain physiology, Magnetic Resonance Imaging
- Abstract
Background/objectives: Obesity affects more than forty percent of adults over the age of sixty. Aberrant eating styles such as disinhibition have been associated with the engagement of brain networks underlying executive functioning, attentional control, and interoception. However, these effects have been exclusively studied in young samples overlooking those most at risk of obesity related harm., Methods: Here we assessed associations between resting-state functional connectivity and disinhibited eating (using the Three Factor Eating Questionnaire) in twenty-one younger (aged 19-34 years, BMI range: 18-31) and twenty older (aged 60-73 years, BMI range: 19-32) adults matched for BMI. The Alternative Healthy Eating Index was used to quantify diet quality., Results: Older, compared to younger, individuals reported lower levels of disinhibited eating, consumed a healthier diet, and had weaker connectivity in the frontoparietal (FPN) and default mode (DMN) networks. In addition, associations between functional connectivity and eating behaviour differed between the two age groups. In older adults, disinhibited eating was associated with weaker connectivity in the FPN and DMN--effects that were absent in the younger sample. Importantly, these effects could not be explained by differences in habitual diet., Conclusions: These findings point to a change in interoceptive signalling as part of the ageing process, which may contribute to behavioural changes in energy intake, and highlight the importance of studying this under researched population., (© 2022. The Author(s).)
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- 2022
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12. Reaction Time Decomposition as a Tool to Study Subcortical Ischemic Vascular Cognitive Impairment.
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Richards E, Tales A, Bayer A, Norris JE, Hanley CJ, and Thornton IM
- Abstract
Background: The study of reaction time (RT) and its intraindividual variability (IIV) in aging, cognitive impairment, and dementia typically fails to investigate the processing stages that contribute to an overall response. Applying "mental chronometry" techniques makes it possible to separately assess the role of processing components during environmental interaction., Objective: To determine whether RT and IIV-decomposition techniques can shed light on the nature of underlying deficits in subcortical ischemic vascular cognitive impairment (VCI). Using a novel iPad task, we examined whether VCI deficits occur during both initiation and movement phases of a response, and whether they are equally reflected in both RT and IIV., Methods: Touch cancellation RT and its IIV were measured in a group of younger adults ( n = 22), cognitively healthy older adults ( n = 21), and patients with VCI ( n = 21) using an iPad task., Results: Whereas cognitively healthy aging affected the speed (RT) of response initiation and movement but not its variability (IIV), VCI resulted in both slowed RT and increased IIV for both response phases. Furthermore, there were group differences with respect to response phase., Conclusion: These results indicate that IIV can be more sensitive than absolute RT in separating VCI from normal aging. Furthermore, compared to cognitively healthy aging, VCI was characterized by significant deficits in planning/initiating action as well as performing movements. Such deficits have important implications for real life actions such as driving safety, employment, and falls risk., Competing Interests: The authors have no conflict of interest to report., (© 2021 – The authors. Published by IOS Press.)
- Published
- 2021
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13. Intratumoral follicular regulatory T cells curtail anti-PD-1 treatment efficacy.
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Eschweiler S, Clarke J, Ramírez-Suástegui C, Panwar B, Madrigal A, Chee SJ, Karydis I, Woo E, Alzetani A, Elsheikh S, Hanley CJ, Thomas GJ, Friedmann PS, Sanchez-Elsner T, Ay F, Ottensmeier CH, and Vijayanand P
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- Animals, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, CD8-Positive T-Lymphocytes immunology, Cell Line, Tumor, Disease Models, Animal, Female, Humans, Mice, Mice, Inbred C57BL, T Follicular Helper Cells immunology, Tumor Microenvironment immunology, CTLA-4 Antigen antagonists & inhibitors, Immune Checkpoint Inhibitors therapeutic use, Lymphocytes, Tumor-Infiltrating immunology, Melanoma drug therapy, Programmed Cell Death 1 Receptor antagonists & inhibitors, T-Lymphocytes, Regulatory immunology
- Abstract
Immune-checkpoint blockade (ICB) has shown remarkable clinical success in boosting antitumor immunity. However, the breadth of its cellular targets and specific mode of action remain elusive. We find that tumor-infiltrating follicular regulatory T (T
FR ) cells are prevalent in tumor tissues of several cancer types. They are primarily located within tertiary lymphoid structures and exhibit superior suppressive capacity and in vivo persistence as compared with regulatory T cells, with which they share a clonal and developmental relationship. In syngeneic tumor models, anti-PD-1 treatment increases the number of tumor-infiltrating TFR cells. Both TFR cell deficiency and the depletion of TFR cells with anti-CTLA-4 before anti-PD-1 treatment improve tumor control in mice. Notably, in a cohort of 271 patients with melanoma, treatment with anti-CTLA-4 followed by anti-PD-1 at progression was associated with better a survival outcome than monotherapy with anti-PD-1 or anti-CTLA-4, anti-PD-1 followed by anti-CTLA-4 at progression or concomitant combination therapy., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)- Published
- 2021
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14. Targeting cancer associated fibroblasts to enhance immunotherapy: emerging strategies and future perspectives.
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Hanley CJ and Thomas GJ
- Abstract
Cancer associated fibroblasts are a prominent component of the tumour microenvironment in most solid cancers. This heterogeneous population of cells are known to play an important role in tumour progression and recent studies have demonstrated that CAFs may confer resistance to checkpoint immunotherapy, suggesting that targeting these cells could improve response rates. However, effective clinical strategies for CAF targeting have yet to be identified. In this editorial, we highlight current limitations in our understanding of CAF heterogeneity, and discuss the potential and possible approaches for CAF-directed therapy., Competing Interests: CONFLICTS OF INTEREST CJ Hanley and GJ Thomas are co-inventors on patent WO2019086579., (Copyright: © 2021 Hanley and Thomas.)
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- 2021
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15. Cancer-Associated Fibroblasts in Oral Cancer: A Current Perspective on Function and Potential for Therapeutic Targeting.
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Bienkowska KJ, Hanley CJ, and Thomas GJ
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The role of the tumour microenvironement (TME) in cancer progression and resistance to therapies is now widely recognized. The most prominent non-immune cell type in the microenvironment of oral cancer (OSCC) is cancer-associated fibroblasts (CAF). Although CAF are a poorly characterised and heterogenous cell population, those with an "activated" myofibroblastic phenotype have been shown to support OSCC progression, promoting growth, invasion and numerous other "hallmarks of malignancy." CAF also confer broad resistance to different types of therapy, including chemo/radiotherapy and EGFR inhibitors; consistent with this, CAF-rich OSCC are associated with poor prognosis. In recent years, much CAF research has focused on their immunological role in the tumour microenvironment, showing that CAF shield tumours from immune attack through multiple mechanisms, and particularly on their role in promoting resistance to anti-PD-1/PD-L1 checkpoint inhibitors, an exciting development for the treatment of recurrent/metastatic oral cancer, but which fails in most patients. This review summarises our current understanding of CAF subtypes and function in OSCC and discusses the potential for targeting these cells therapeutically., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bienkowska, Hanley and Thomas.)
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- 2021
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16. Visual Attention-Related Processing: Perspectives from Ageing, Cognitive Decline and Dementia.
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Hanley CJ and Tales A
- Abstract
Regarded as a defining factor in resource management, it is widely accepted that visual attention and related processing will deteriorate, in a global fashion, across the lifespan and produce detrimental consequences for environmental interactions [...].
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- 2021
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17. Tumor-Resident Stromal Cells Promote Breast Cancer Invasion through Regulation of the Basal Phenotype.
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Hanley CJ, Henriet E, Sirka OK, Thomas GJ, and Ewald AJ
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- Animals, Female, Humans, Mice, Neoplasm Invasiveness, Phenotype, Breast Neoplasms genetics, Computational Biology methods, Stromal Cells metabolism
- Abstract
Collective invasion can be led by breast cancer cells expressing basal epithelial markers, typified by keratin-14 (KRT14). We analyzed gene expression data from The Cancer Genome Atlas and demonstrated a significant correlation between a KRT14
+ invasion signature and a stromal-mediated extracellular matrix (ECM) organization module. We then developed a novel coculture model of tumor organoids with autologous stromal cells. Coculture significantly increased KRT14 expression and invasion of organoids from both luminal and basal murine breast cancer models. However, stromal cell conditioned medium induced invasion but not KRT14 expression. Cancer cells released TGFβ and that signaling pathway was required for stromal cell-induced invasion and KRT14 expression. Mechanistically, TGFβ induced NOX4 expression in stromal cells and NOX4 inhibition reduced invasion and KRT14 expression. In summary, we developed a novel coculture model and revealed dynamic molecular interactions between stromal cells and cancer cells that regulate both basal gene expression and invasive behavior. IMPLICATIONS: Fibroblasts within mammary tumors can regulate the molecular phenotype and invasive behavior of breast cancer cells. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/18/11/1615/F1.large.jpg., (©2020 American Association for Cancer Research.)- Published
- 2020
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18. CTEN Induces Tumour Cell Invasion and Survival and Is Prognostic in Radiotherapy-Treated Head and Neck Cancer.
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Fleming JC, Woo J, Moutasim K, Hanley CJ, Frampton SJ, Wood O, Ward M, Woelk CH, Ottensmeier CH, Hafizi S, Kim D, and Thomas GJ
- Abstract
Head and neck squamous cell carcinoma (HNSCC) is a heterogenous disease treated with surgery and/or (chemo) radiotherapy, but up to 50% of patients with late-stage disease develop locoregional recurrence. Determining the mechanisms underpinning treatment resistance could identify new therapeutic targets and aid treatment selection. C-terminal tensin-like (CTEN) is a member of the tensin family, upregulated in several cancers, although its expression and function in HNSCC are unknown. We found that CTEN is commonly upregulated in HNSCC, particularly HPV
-ve tumours. In vitro CTEN was upregulated in HPV-ve ( n = 5) and HPV+ve ( n = 2) HNSCC cell lines. Stable shRNA knockdown of CTEN in vivo significantly reduced tumour growth (SCC-25), and functional analyses in vitro showed that CTEN promoted tumour cell invasion, colony formation and growth in 3D-culture (SCC-25, Detroit 562). RNA sequencing of SCC-25 cells following CTEN siRNA knockdown identified 349 differentially expressed genes (logFC > 1, p < 0.05). Gene ontology analysis highlighted terms relating to cell locomotion and apoptosis, consistent with in vitro findings. A membrane-based antibody array confirmed that CTEN regulated multiple apoptosis-associated proteins, including HSP60 and cleaved caspase-3. Notably, in a mixed cohort of HPV+ve and HPV-ve HNSCC patients ( n = 259), we found a significant, independent negative association of CTEN with prognosis, limited to those patients treated with (chemo)radiotherapy, not surgery, irrespective of human papillomavirus (HPV) status. These data show that CTEN is commonly upregulated in HNSCC and exerts several functional effects. Its potential role in modulating apoptotic response to therapy suggests utility as a predictive biomarker or radio-sensitising target.- Published
- 2020
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19. T-cell tumour exclusion and immunotherapy resistance: a role for CAF targeting.
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Hanley CJ and Thomas GJ
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- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cancer-Associated Fibroblasts pathology, Cancer-Associated Fibroblasts physiology, Drug Synergism, Humans, Immunotherapy, Molecular Targeted Therapy trends, NADPH Oxidase 4 antagonists & inhibitors, Neoplasms pathology, Neoplasms therapy, Pyrazolones administration & dosage, Pyridones administration & dosage, T-Lymphocytes drug effects, T-Lymphocytes immunology, Tumor Microenvironment drug effects, Tumor Microenvironment immunology, Antineoplastic Agents, Immunological therapeutic use, Cancer-Associated Fibroblasts drug effects, Drug Resistance, Neoplasm drug effects, Molecular Targeted Therapy methods, Pyrazolones pharmacology, Pyridones pharmacology, T-Lymphocytes pathology
- Abstract
Recent studies have highlighted a major role for cancer-associated fibroblasts (CAFs) in promoting immunotherapy resistance by excluding T cells from tumours. Recently, we showed that CAFs can be effectively targeted by inhibiting the enzyme NOX4; this 'normalises' CAFs and overcomes immunotherapy resistance. Here we discuss our study and other strategies for CAF targeting.
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- 2020
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20. Lacking Pace but Not Precision: Age-Related Information Processing Changes in Response to a Dynamic Attentional Control Task.
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Torrens-Burton A, Hanley CJ, Wood R, Basoudan N, Norris JE, Richards E, and Tales A
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Age-related decline in information processing can have a substantial impact on activities such as driving. However, the assessment of these changes is often carried out using cognitive tasks that do not adequately represent the dynamic process of updating environmental stimuli. Equally, traditional tests are often static in their approach to task complexity, and do not assess difficulty within the bounds of an individual's capability. To address these limitations, we used a more ecologically valid measure, the Swansea Test of Attentional Control (STAC), in which a threshold for information processing speed is established at a given level of accuracy. We aimed to delineate how older, compared to younger, adults varied in their performance of the task, while also assessing relationships between the task outcome and gender, general cognition (MoCA), perceived memory function (MFQ), cognitive reserve (NART), and aspects of mood (PHQ-9, GAD-7). The results indicate that older adults were significantly slower than younger adults but no less precise, irrespective of gender. Age was negatively correlated with the speed of task performance. Our measure of general cognition was positively correlated with the task speed threshold but not with age per se. Perceived memory function, cognitive reserve, and mood were not related to task performance. The findings indicate that while attentional control is less efficient in older adulthood, age alone is not a defining factor in relation to accuracy. In a real-life context, general cognitive function, in conjunction with dynamic measures such as STAC, may represent a far more effective strategy for assessing the complex executive functions underlying driving ability.
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- 2020
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21. Optimising Cognitive Enhancement: Systematic Assessment of the Effects of tDCS Duration in Older Adults.
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Hanley CJ, Alderman SL, and Clemence E
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Transcranial direct current stimulation (tDCS) has been shown to support cognition and brain function in older adults. However, there is an absence of research specifically designed to determine optimal stimulation protocols, and much of what is known about subtle distinctions in tDCS parameters is based on young adult data. As the first systematic exploration targeting older adults, this study aimed to provide insight into the effects of variations in stimulation duration. Anodal stimulation of 10 and 20 min, as well as a sham-control variant, was administered to dorsolateral prefrontal cortex. Stimulation effects were assessed in relation to a novel attentional control task. Ten minutes of anodal stimulation significantly improved task-switching speed from baseline, contrary to the sham-control and 20 min variants. The findings represent a crucial step forwards for methods development, and the refinement of stimulation to enhance executive function in the ageing population., Competing Interests: The authors declare no conflict of interest.
- Published
- 2020
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22. NOX4 Inhibition Potentiates Immunotherapy by Overcoming Cancer-Associated Fibroblast-Mediated CD8 T-cell Exclusion from Tumors.
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Ford K, Hanley CJ, Mellone M, Szyndralewiez C, Heitz F, Wiesel P, Wood O, Machado M, Lopez MA, Ganesan AP, Wang C, Chakravarthy A, Fenton TR, King EV, Vijayanand P, Ottensmeier CH, Al-Shamkhani A, Savelyeva N, and Thomas GJ
- Subjects
- Animals, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Humans, Immunotherapy, Mice, NADPH Oxidase 4, Reactive Oxygen Species, Cancer-Associated Fibroblasts, Neoplasms
- Abstract
Determining mechanisms of resistance to αPD-1/PD-L1 immune-checkpoint immunotherapy is key to developing new treatment strategies. Cancer-associated fibroblasts (CAF) have many tumor-promoting functions and promote immune evasion through multiple mechanisms, but as yet, no CAF-specific inhibitors are clinically available. Here we generated CAF-rich murine tumor models (TC1, MC38, and 4T1) to investigate how CAFs influence the immune microenvironment and affect response to different immunotherapy modalities [anticancer vaccination, TC1 (HPV E7 DNA vaccine), αPD-1, and MC38] and found that CAFs broadly suppressed response by specifically excluding CD8
+ T cells from tumors (not CD4+ T cells or macrophages); CD8+ T-cell exclusion was similarly present in CAF-rich human tumors. RNA sequencing of CD8+ T cells from CAF-rich murine tumors and immunochemistry analysis of human tumors identified significant upregulation of CTLA-4 in the absence of other exhaustion markers; inhibiting CTLA-4 with a nondepleting antibody overcame the CD8+ T-cell exclusion effect without affecting Tregs. We then examined the potential for CAF targeting, focusing on the ROS-producing enzyme NOX4, which is upregulated by CAF in many human cancers, and compared this with TGFβ1 inhibition, a key regulator of the CAF phenotype. siRNA knockdown or pharmacologic inhibition [GKT137831 (Setanaxib)] of NOX4 "normalized" CAF to a quiescent phenotype and promoted intratumoral CD8+ T-cell infiltration, overcoming the exclusion effect; TGFβ1 inhibition could prevent, but not reverse, CAF differentiation. Finally, NOX4 inhibition restored immunotherapy response in CAF-rich tumors. These findings demonstrate that CAF-mediated immunotherapy resistance can be effectively overcome through NOX4 inhibition and could improve outcome in a broad range of cancers. SIGNIFICANCE: NOX4 is critical for maintaining the immune-suppressive CAF phenotype in tumors. Pharmacologic inhibition of NOX4 potentiates immunotherapy by overcoming CAF-mediated CD8+ T-cell exclusion. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/9/1846/F1.large.jpg. See related commentary by Hayward, p. 1799 ., (©2020 American Association for Cancer Research.)- Published
- 2020
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23. An Optimized Method to Isolate Human Fibroblasts from Tissue for ex vivo Analysis.
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Waise S, Parker R, Rose-Zerilli MJJ, Layfield DM, Wood O, West J, Ottensmeier CH, Thomas GJ, and Hanley CJ
- Abstract
Despite their involvement in many physiological and pathological processes, fibroblasts remain a poorly-characterized cell type. Analysis of primary fibroblasts while maintaining their in vivo phenotype is challenging: standard methods for fibroblast isolation require cell culture in vitro , which is known to alter phenotypes. Previously-described protocols for the dissociation of primary tissues fail to extract sufficient numbers of fibroblasts, instead largely yielding immune cells. Here, we describe an optimized method for generating a fibroblast-enriched single-cell suspension from human tissues using combined mechanical and enzymatic dissociation. This allows analysis of ex vivo fibroblasts without the need for culture in vitro ., Competing Interests: Competing interestsThe authors declare no competing interests., (Copyright © 2019 The Authors; exclusive licensee Bio-protocol LLC.)
- Published
- 2019
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24. Single-cell transcriptomic analysis of tissue-resident memory T cells in human lung cancer.
- Author
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Clarke J, Panwar B, Madrigal A, Singh D, Gujar R, Wood O, Chee SJ, Eschweiler S, King EV, Awad AS, Hanley CJ, McCann KJ, Bhattacharyya S, Woo E, Alzetani A, Seumois G, Thomas GJ, Ganesan AP, Friedmann PS, Sanchez-Elsner T, Ay F, Ottensmeier CH, and Vijayanand P
- Subjects
- Cell Proliferation, Clone Cells, Cytotoxicity, Immunologic genetics, Hepatitis A Virus Cellular Receptor 2 metabolism, Humans, Lung metabolism, Lung pathology, Lymphocyte Subsets immunology, Lymphocytes, Tumor-Infiltrating immunology, Programmed Cell Death 1 Receptor metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Transcription, Genetic, Gene Expression Profiling, Immunologic Memory genetics, Lung Neoplasms genetics, Lung Neoplasms immunology, Single-Cell Analysis, T-Lymphocytes immunology, Transcriptome genetics
- Abstract
High numbers of tissue-resident memory T (T
RM ) cells are associated with better clinical outcomes in cancer patients. However, the molecular characteristics that drive their efficient immune response to tumors are poorly understood. Here, single-cell and bulk transcriptomic analysis of TRM and non-TRM cells present in tumor and normal lung tissue from patients with lung cancer revealed that PD-1-expressing TRM cells in tumors were clonally expanded and enriched for transcripts linked to cell proliferation and cytotoxicity when compared with PD-1-expressing non-TRM cells. This feature was more prominent in the TRM cell subset coexpressing PD-1 and TIM-3, and it was validated by functional assays ex vivo and also reflected in their chromatin accessibility profile. This PD-1+ TIM-3+ TRM cell subset was enriched in responders to PD-1 inhibitors and in tumors with a greater magnitude of CTL responses. These data highlight that not all CTLs expressing PD-1 are dysfunctional; on the contrary, TRM cells with PD-1 expression were enriched for features suggestive of superior functionality., (© 2019 Clarke et al.)- Published
- 2019
- Full Text
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25. An optimised tissue disaggregation and data processing pipeline for characterising fibroblast phenotypes using single-cell RNA sequencing.
- Author
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Waise S, Parker R, Rose-Zerilli MJJ, Layfield DM, Wood O, West J, Ottensmeier CH, Thomas GJ, and Hanley CJ
- Subjects
- Cells, Cultured, Cluster Analysis, Collagenases metabolism, Epithelial Cell Adhesion Molecule metabolism, Fibroblasts cytology, Humans, Leukocyte Common Antigens metabolism, Lung cytology, Phenotype, Single-Cell Analysis, Stromal Cells cytology, Stromal Cells metabolism, Transcriptome, Fibroblasts metabolism, Sequence Analysis, RNA methods
- Abstract
Single-cell RNA sequencing (scRNA-Seq) provides a valuable platform for characterising multicellular ecosystems. Fibroblasts are a heterogeneous cell type involved in many physiological and pathological processes, but remain poorly-characterised. Analysis of fibroblasts is challenging: these cells are difficult to isolate from tissues, and are therefore commonly under-represented in scRNA-seq datasets. Here, we describe an optimised approach for fibroblast isolation from human lung tissues. We demonstrate the potential for this procedure in characterising stromal cell phenotypes using scRNA-Seq, analyse the effect of tissue disaggregation on gene expression, and optimise data processing to improve clustering quality. We also assess the impact of in vitro culture conditions on stromal cell gene expression and proliferation, showing that altering these conditions can skew phenotypes.
- Published
- 2019
- Full Text
- View/download PDF
26. Towards Establishing Age-Related Cortical Plasticity on the Basis of Somatosensation.
- Author
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Hanley CJ, Burianová H, and Tommerdahl M
- Subjects
- Adult, Age Factors, Aged, Female, Humans, Middle Aged, Physical Stimulation, Reaction Time physiology, Touch physiology, Vibration, Adaptation, Physiological physiology, Discrimination, Psychological physiology, Touch Perception physiology
- Abstract
Age-related somatosensory processing appears to remain intact where tasks engage centrally- as opposed to peripherally-mediated mechanisms. This distinction suggests that insight into alterations in neural plasticity could be derived via metrics of vibrotactile performance. Such an approach could be used to support the early detection of global changes in brain health but current evidence is limited. Knowledge of the precise conditions in which older adults are expected to sustain somatosensory performance is largely unknown. For this purpose, the study aimed to characterize age-related performance on tactile detection and discrimination-based tests. Accordingly, a group of young and older adult participants took part in simple reaction time and amplitude discrimination tasks. Participants' ability to distinguish between stimuli on the basis of amplitude was assessed with and without dual-site adaptation, which has been proposed to refine cortical responses and improve behavioral performance. The results show that while older adults exhibited significantly prolonged (p < .001, d = 1.116) and more variable (p = .022, d = 0.578) information processing speed compared to young adults, they were able to achieve similar scores in baseline discrimination (p = .179, d = 0.336). We also report, for the first time, that older adults displayed similar performance improvements to young adults, under conditions of dual-site adaptation (p = .948, d = 0.016). The findings support the argument that centrally-mediated mechanisms remain intact in the ageing population. Accordingly, dual-site adaptation data provide compelling new evidence of somatosensation in ageing that will contribute towards the development of an assessment tool to ascertain pre-clinical, age-related changes in the status of cortical function., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
27. Anodal tDCS improves attentional control in older adults.
- Author
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Hanley CJ and Tales A
- Subjects
- Aged, Aging physiology, Double-Blind Method, Female, Humans, Male, Middle Aged, Psychomotor Performance, Attention, Brain physiology, Executive Function, Neuronal Plasticity, Transcranial Direct Current Stimulation methods
- Abstract
Transcranial direct current stimulation (tDCS) facilitates cognitive enhancement by directly increasing neuroplasticity, and has shown promising results as an external intervention to attenuate age-related cognitive decline. However, stimulation protocols have failed to account for age-associated changes in brain structure and the present literature omits investigation of attentional control, despite the occurrence of substantial inhibitory processing deficits with age. To provide new insight into the benefits of tDCS, the objective of this study was to develop an age-optimised stimulation protocol in which key parameters (amplitude, duration, and electrode configuration) were selected in accordance with knowledge of stimulation effects, specific to the ageing brain. Participants (mean age 66.5 years) completed three sessions of double-blind, anodal or sham stimulation, in conjunction with a novel task switching paradigm, which was designed to reflect the complexities of simultaneously monitoring and updating stimulus representations. The results show that those who had anodal tDCS exhibited an acute, post-stimulation increase in task switching speed (p < .01, d = 1.36). Although the sham group was subject to the same task exposure, only the anodal stimulation group experienced a performance gain, thus emphasising the efficacy of active brain stimulation. For the first time, this study demonstrates the utility of stimulation protocols tailored specifically for use with older adults, targeted towards the modulation of attentional control. This finding has critical implications for cognitive health and encourages the use of age-optimised tDCS as a viable method for enhancing executive function in later life., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2019
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28. PTBP1-Mediated Alternative Splicing Regulates the Inflammatory Secretome and the Pro-tumorigenic Effects of Senescent Cells.
- Author
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Georgilis A, Klotz S, Hanley CJ, Herranz N, Weirich B, Morancho B, Leote AC, D'Artista L, Gallage S, Seehawer M, Carroll T, Dharmalingam G, Wee KB, Mellone M, Pombo J, Heide D, Guccione E, Arribas J, Barbosa-Morais NL, Heikenwalder M, Thomas GJ, Zender L, and Gil J
- Subjects
- Alternative Splicing, Animals, Cell Proliferation, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic pathology, Female, Gene Expression Regulation, Neoplastic, Heterogeneous-Nuclear Ribonucleoproteins genetics, Humans, Inflammation genetics, Inflammation pathology, Inflammation therapy, MCF-7 Cells, Mice, Inbred C57BL, Mice, Transgenic, Neoplasms genetics, Neoplasms pathology, Neoplasms prevention & control, Paracrine Communication, Phenotype, Polypyrimidine Tract-Binding Protein genetics, RNA Interference, Signal Transduction, Tumor Burden, Vesicular Transport Proteins genetics, Vesicular Transport Proteins metabolism, Cell Transformation, Neoplastic metabolism, Cellular Senescence, Heterogeneous-Nuclear Ribonucleoproteins metabolism, Inflammation metabolism, Neoplasms metabolism, Polypyrimidine Tract-Binding Protein metabolism
- Abstract
Oncogene-induced senescence is a potent tumor-suppressive response. Paradoxically, senescence also induces an inflammatory secretome that promotes carcinogenesis and age-related pathologies. Consequently, the senescence-associated secretory phenotype (SASP) is a potential therapeutic target. Here, we describe an RNAi screen for SASP regulators. We identified 50 druggable targets whose knockdown suppresses the inflammatory secretome and differentially affects other SASP components. Among the screen candidates was PTBP1. PTBP1 regulates the alternative splicing of genes involved in intracellular trafficking, such as EXOC7, to control the SASP. Inhibition of PTBP1 prevents the pro-tumorigenic effects of the SASP and impairs immune surveillance without increasing the risk of tumorigenesis. In conclusion, our study identifies SASP inhibition as a powerful and safe therapy against inflammation-driven cancer., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
29. Targeting the Myofibroblastic Cancer-Associated Fibroblast Phenotype Through Inhibition of NOX4.
- Author
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Hanley CJ, Mellone M, Ford K, Thirdborough SM, Mellows T, Frampton SJ, Smith DM, Harden E, Szyndralewiez C, Bullock M, Noble F, Moutasim KA, King EV, Vijayanand P, Mirnezami AH, Underwood TJ, Ottensmeier CH, and Thomas GJ
- Subjects
- Actins analysis, Adenocarcinoma chemistry, Adenocarcinoma genetics, Adult, Aged, Aged, 80 and over, Animals, Cancer-Associated Fibroblasts chemistry, Cancer-Associated Fibroblasts physiology, Carcinoma, Non-Small-Cell Lung chemistry, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Squamous Cell chemistry, Carcinoma, Squamous Cell genetics, Cell Count, Cell Transdifferentiation drug effects, Cell Transdifferentiation genetics, Colorectal Neoplasms pathology, Disease Progression, Esophageal Neoplasms chemistry, Esophageal Neoplasms genetics, Female, Head and Neck Neoplasms chemistry, Head and Neck Neoplasms drug therapy, Head and Neck Neoplasms genetics, Humans, Lung Neoplasms chemistry, Lung Neoplasms genetics, Male, Mice, Middle Aged, Mouth Neoplasms pathology, Myofibroblasts chemistry, NADPH Oxidase 4, NADPH Oxidases analysis, NADPH Oxidases genetics, Neoplasm Transplantation, Oropharyngeal Neoplasms pathology, Phenotype, Pyrazoles therapeutic use, Pyrazolones, Pyridines therapeutic use, Pyridones, RNA Interference, Reactive Oxygen Species metabolism, Survival Rate, Up-Regulation, Adenocarcinoma drug therapy, Cancer-Associated Fibroblasts pathology, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Squamous Cell drug therapy, Colorectal Neoplasms chemistry, Esophageal Neoplasms drug therapy, Lung Neoplasms drug therapy, Mouth Neoplasms chemistry, Myofibroblasts pathology, NADPH Oxidases antagonists & inhibitors, Oropharyngeal Neoplasms chemistry
- Abstract
Background: Cancer-associated fibroblasts (CAFs) are tumor-promoting and correlate with poor survival in many cancers, which has led to their emergence as potential therapeutic targets. However, effective methods to manipulate these cells clinically have yet to be developed., Methods: CAF accumulation and prognostic significance in head and neck cancer (oral, n = 260; oropharyngeal, n = 271), and colorectal cancer (n = 56) was analyzed using immunohistochemistry. Mechanisms regulating fibroblast-to-myofibroblast transdifferentiation were investigated in vitro using RNA interference/pharmacological inhibitors followed by polymerase chain reaction (PCR), immunoblotting, immunofluorescence, and functional assays. RNA sequencing/bioinformatics and immunohistochemistry were used to analyze NAD(P)H Oxidase-4 (NOX4) expression in different human tumors. NOX4's role in CAF-mediated tumor progression was assessed in vitro, using CAFs from multiple tissues in Transwell and organotypic culture assays, and in vivo, using xenograft (n = 9-15 per group) and isograft (n = 6 per group) tumor models. All statistical tests were two-sided., Results: Patients with moderate/high levels of myofibroblastic-CAF had a statistically significant decrease in cancer-specific survival rates in each cancer type analyzed (hazard ratios [HRs] = 1.69-7.25, 95% confidence intervals [CIs] = 1.11 to 31.30, log-rank P ≤ .01). Fibroblast-to-myofibroblast transdifferentiation was dependent on a delayed phase of intracellular reactive oxygen species, generated by NOX4, across different anatomical sites and differentiation stimuli. A statistically significant upregulation of NOX4 expression was found in multiple human cancers (P < .001), strongly correlating with myofibroblastic-CAFs (r = 0.65-0.91, adjusted P < .001). Genetic/pharmacological inhibition of NOX4 was found to revert the myofibroblastic-CAF phenotype ex vivo (54.3% decrease in α-smooth muscle actin [α-SMA], 95% CI = 10.6% to 80.9%, P = .009), prevent myofibroblastic-CAF accumulation in vivo (53.2%-79.0% decrease in α-SMA across different models, P ≤ .02) and slow tumor growth (30.6%-64.0% decrease across different models, P ≤ .04)., Conclusions: These data suggest that pharmacological inhibition of NOX4 may have broad applicability for stromal targeting across cancer types., (© The Author 2017. Published by Oxford University Press.)
- Published
- 2018
- Full Text
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30. Pro-migratory and TGF-β-activating functions of αvβ6 integrin in pancreatic cancer are differentially regulated via an Eps8-dependent GTPase switch.
- Author
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Tod J, Hanley CJ, Morgan MR, Rucka M, Mellows T, Lopez MA, Kiely P, Moutasim KA, Frampton SJ, Sabnis D, Fine DR, Johnson C, Marshall JF, Scita G, Jenei V, and Thomas GJ
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Antigens, Neoplasm genetics, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal pathology, Cell Line, Tumor, Coculture Techniques, Cytoskeletal Proteins genetics, Cytoskeletal Proteins metabolism, Enzyme Inhibitors pharmacology, Humans, Integrins genetics, Neoplasm Invasiveness, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Phenotype, RNA Interference, SOS1 Protein genetics, SOS1 Protein metabolism, Signal Transduction, Stromal Cells enzymology, Stromal Cells pathology, Transfection, Tumor Microenvironment, rac1 GTP-Binding Protein genetics, rho GTP-Binding Proteins antagonists & inhibitors, Adaptor Proteins, Signal Transducing metabolism, Antigens, Neoplasm metabolism, Carcinoma, Pancreatic Ductal enzymology, Cell Movement drug effects, Integrins metabolism, Pancreatic Neoplasms enzymology, Transforming Growth Factor beta1 metabolism, rac1 GTP-Binding Protein metabolism, rho GTP-Binding Proteins metabolism
- Abstract
The integrin αvβ6 is up-regulated in numerous carcinomas, where expression commonly correlates with poor prognosis. αvβ6 promotes tumour invasion, partly through regulation of proteases and cell migration, and is also the principal mechanism by which epithelial cells activate TGF-β1; this latter function complicates therapeutic targeting of αvβ6, since TGF-β1 has both tumour-promoting and -suppressive effects. It is unclear how these different αvβ6 functions are linked; both require actin cytoskeletal reorganization, and it is suggested that tractive forces generated during cell migration activate TGF-β1 by exerting mechanical tension on the ECM-bound latent complex. We examined the functional relationship between cell invasion and TGF-β1 activation in pancreatic ductal adenocarcinoma (PDAC) cells, and confirmed that both processes are αvβ6-dependent. Surprisingly, we found that cellular functions could be biased towards either motility or TGF-β1 activation depending on the presence or absence of epidermal growth factor receptor pathway substrate 8 (Eps8), a regulator of actin remodelling, endocytosis, and GTPase activation. Similar to αvβ6, we found that Eps8 was up-regulated in >70% of PDACs. In complex with Abi1/Sos1, Eps8 regulated αvβ6-dependent cell migration through activation of Rac1. Down-regulation of Eps8, Sos1 or Rac1 suppressed cell movement, while simultaneously increasing αvβ6-dependent TGF-β1 activation. This latter effect was modulated through increased cell tension, regulated by Rho activation. Thus, the Eps8/Abi1/Sos1 tricomplex acts as a key molecular switch altering the balance between Rac1 and Rho activation; its presence or absence in PDAC cells modulates αvβ6-dependent functions, resulting in a pro-migratory (Rac1-dependent) or a pro-TGF-β1 activation (Rho-dependent) functional phenotype, respectively. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland., (© 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.)
- Published
- 2017
- Full Text
- View/download PDF
31. Induction of fibroblast senescence generates a non-fibrogenic myofibroblast phenotype that differentially impacts on cancer prognosis.
- Author
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Mellone M, Hanley CJ, Thirdborough S, Mellows T, Garcia E, Woo J, Tod J, Frampton S, Jenei V, Moutasim KA, Kabir TD, Brennan PA, Venturi G, Ford K, Herranz N, Lim KP, Clarke J, Lambert DW, Prime SS, Underwood TJ, Vijayanand P, Eliceiri KW, Woelk C, King EV, Gil J, Ottensmeier CH, and Thomas GJ
- Subjects
- Animals, Cell Line, Tumor, Extracellular Matrix metabolism, Fibroblasts metabolism, Humans, Mice, Myofibroblasts metabolism, Neoplasms metabolism, Phenotype, Prognosis, Signal Transduction physiology, Transforming Growth Factor beta1 metabolism, Cell Differentiation physiology, Cellular Senescence physiology, Fibroblasts pathology, Myofibroblasts pathology, Neoplasms pathology
- Abstract
Cancer-associated fibroblasts (CAF) remain a poorly characterized, heterogeneous cell population. Here we characterized two previously described tumor-promoting CAF sub-types, smooth muscle actin (SMA)-positive myofibroblasts and senescent fibroblasts, identifying a novel link between the two. Analysis of CAF cultured ex vivo , showed that senescent CAF are predominantly SMA-positive; this was confirmed by immunochemistry in head & neck (HNSCC) and esophageal (EAC) cancers. In vitro , we found that fibroblasts induced to senesce develop molecular, ultrastructural and contractile features typical of myofibroblasts and this is dependent on canonical TGF-β signaling. Similar to TGF-β1-generated myofibroblasts, these cells secrete soluble factors that promote tumor cell motility. However, RNA-sequencing revealed significant transcriptomic differences between the two SMA-positive CAF groups, particularly in genes associated with extracellular matrix (ECM) deposition and organization, which differentially promote tumor cell invasion. Notably, second harmonic generation imaging and bioinformatic analysis of SMA-positive human HNSCC and EAC showed that collagen fiber organization correlates with poor prognosis, indicating that heterogeneity within the SMA-positive CAF population differentially impacts on survival. These results show that non-fibrogenic, SMA-positive myofibroblasts can be directly generated through induction of fibroblast senescence and suggest that senescence and myofibroblast differentiation are closely linked processes.
- Published
- 2016
- Full Text
- View/download PDF
32. Transcranial modulation of brain oscillatory responses: A concurrent tDCS-MEG investigation.
- Author
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Hanley CJ, Singh KD, and McGonigle DJ
- Subjects
- Adult, Brain Mapping methods, Female, Humans, Male, Motor Cortex physiology, Visual Cortex physiology, Beta Rhythm physiology, Biological Clocks physiology, Evoked Potentials, Motor physiology, Gamma Rhythm physiology, Magnetoencephalography methods, Psychomotor Performance physiology, Transcranial Direct Current Stimulation methods
- Abstract
Despite the increasing use of transcranial direct current stimulation (tDCS), the physiological mechanisms underlying its effects are still largely unknown. One approach to directly investigate the effects of the neuromodulation technique on the brain is to integrate tDCS with non-invasive neuroimaging in humans. To provide new insight into the neurobiology of the method, DC stimulation (1mA, 600s) was applied concurrently with Magnetoencephalography (MEG), while participants engaged in a visuomotor task before, during and after a period of tDCS. Responses in the motor beta band (15-30Hz) and visual gamma band (30-80Hz) were localised using Synthetic Aperture Magnetometry (SAM). The resulting induced and evoked oscillatory responses were subsequently analysed. A statistically significant reduction of average power in the visual gamma band was observed for anodal compared to sham stimulation. The magnitude of motor evoked responses was also found to be significantly modulated by anodal stimulation. These results demonstrate that MEG can be used to derive inferences on the cortical mechanisms of tDCS., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
33. Commentary: Systematic assessment of duration and intensity of anodal transcranial direct current stimulation on primary motor cortex excitability.
- Author
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Hanley CJ
- Published
- 2016
- Full Text
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34. A subset of myofibroblastic cancer-associated fibroblasts regulate collagen fiber elongation, which is prognostic in multiple cancers.
- Author
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Hanley CJ, Noble F, Ward M, Bullock M, Drifka C, Mellone M, Manousopoulou A, Johnston HE, Hayden A, Thirdborough S, Liu Y, Smith DM, Mellows T, Kao WJ, Garbis SD, Mirnezami A, Underwood TJ, Eliceiri KW, and Thomas GJ
- Subjects
- Humans, Neoplasms pathology, Prognosis, Survival Rate, Tumor Microenvironment, Cancer-Associated Fibroblasts metabolism, Collagen metabolism, Extracellular Matrix metabolism, Fibroblasts metabolism, Myofibroblasts metabolism, Neoplasms metabolism
- Abstract
Collagen structure has been shown to influence tumor cell invasion, metastasis and clinical outcome in breast cancer. However, it remains unclear how it affects other solid cancers. Here we utilized multi-photon laser scanning microscopy and Second Harmonic Generation to identify alterations to collagen fiber structure within the tumor stroma of head & neck, esophageal and colorectal cancers. Image segmentation algorithms were then applied to quantitatively characterize these morphological changes, showing that elongated collagen fibers significantly correlated with poor clinical outcome (Log Rank p < 0.05). We used TGF-β treatment to model fibroblast conversion to smooth muscle actin SMA-positive cancer associated fibroblasts (CAFs) and found that these cells induce the formation of elongated collagen fibers in vivo. However, proteomic/transcriptomic analysis of SMA-positive CAFs cultured ex-vivo showed significant heterogeneity in the expression of genes with collagen fibril organizing gene ontology. Notably, stratifying patients according to stromal SMA-positivity and collagen fiber elongation was found to provide a highly significant correlation with poor survival in all 3 cancer types (Log Rank p ≤ 0.003). In summary, we show that increased collagen fiber length correlates with poor patient survival in multiple tumor types and that only a sub-set of SMA-positive CAFs can mediate the formation of this collagen structure.
- Published
- 2016
- Full Text
- View/download PDF
35. Stimulating somatosensory psychophysics: a double-blind, sham-controlled study of the neurobiological mechanisms of tDCS.
- Author
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Hanley CJ, Tommerdahl M, and McGonigle DJ
- Abstract
The neuromodulation technique transcranial direct current stimulation (tDCS) is thought to produce its effects on behavior by altering cortical excitability. Although the mechanisms underlying the observed effects are thought to rely on the balance of excitatory and inhibitory neurotransmission, the physiological principles of the technique are not completely understood. In this study, we examine the influence of tDCS on vibrotactile adaptation, using a simple amplitude discrimination paradigm that has been shown to exhibit modifications in performance due to changes in inhibitory neurotransmission. Double-blind tDCS (Anodal/Sham) of 1 mA was delivered for 600 s to electrodes positioned in a somatosensory/contralateral orbit montage. Stimulation was applied as part of a pre/post design, between blocks of the behavioral tasks. In accordance with previous work, results obtained before the application of tDCS indicated that amplitude discrimination thresholds were significantly worsened during adaptation trials, compared to those achieved at baseline. However, tDCS failed to modify amplitude discrimination performance. Using a Bayesian approach, this finding was revealed to constitute substantial evidence for the null hypothesis. The failure of DC stimulation to alter vibrotactile adaptation thresholds is discussed in the context of several factors that may have confounded the induction of changes in cortical plasticity.
- Published
- 2015
- Full Text
- View/download PDF
36. Erratum: mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype.
- Author
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Herranz N, Gallage S, Mellone M, Wuestefeld T, Klotz S, Hanley CJ, Raguz S, Acosta JC, Innes AJ, Banito A, Georgilis A, Montoya A, Wolter K, Dharmalingam G, Faull P, Carroll T, Martínez-Barbera JP, Cutillas P, Reisinger F, Heikenwalder M, Miller RA, Withers D, Zender L, Thomas GJ, and Gil J
- Published
- 2015
- Full Text
- View/download PDF
37. mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype.
- Author
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Herranz N, Gallage S, Mellone M, Wuestefeld T, Klotz S, Hanley CJ, Raguz S, Acosta JC, Innes AJ, Banito A, Georgilis A, Montoya A, Wolter K, Dharmalingam G, Faull P, Carroll T, Martínez-Barbera JP, Cutillas P, Reisinger F, Heikenwalder M, Miller RA, Withers D, Zender L, Thomas GJ, and Gil J
- Subjects
- Animals, Cell Line, Tumor, Cellular Senescence, Female, HEK293 Cells, Humans, Intracellular Signaling Peptides and Proteins genetics, Mice, Nude, Neoplasm Transplantation, Protein Serine-Threonine Kinases genetics, Intracellular Signaling Peptides and Proteins metabolism, Phosphoproteins metabolism, Protein Biosynthesis, Protein Serine-Threonine Kinases metabolism, Proteome metabolism, TOR Serine-Threonine Kinases physiology
- Abstract
Senescent cells secrete a combination of factors collectively known as the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence and activates an immune surveillance response, but it can also show pro-tumorigenic properties and contribute to age-related pathologies. In a drug screen to find new SASP regulators, we uncovered the mTOR inhibitor rapamycin as a potent SASP suppressor. Here we report a mechanism by which mTOR controls the SASP by differentially regulating the translation of the MK2 (also known as MAPKAPK2) kinase through 4EBP1. In turn, MAPKAPK2 phosphorylates the RNA-binding protein ZFP36L1 during senescence, inhibiting its ability to degrade the transcripts of numerous SASP components. Consequently, mTOR inhibition or constitutive activation of ZFP36L1 impairs the non-cell-autonomous effects of senescent cells in both tumour-suppressive and tumour-promoting contexts. Altogether, our results place regulation of the SASP as a key mechanism by which mTOR could influence cancer, age-related diseases and immune responses.
- Published
- 2015
- Full Text
- View/download PDF
38. Misconception: human papillomavirus vaccine and infertility.
- Author
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Schuler CL, Hanley CJ, and Coyne-Beasley T
- Subjects
- Adolescent, Adult, Child, Cross-Sectional Studies, Female, Health Care Surveys, Humans, Intention, Logistic Models, Male, Multivariate Analysis, Parents education, Vaccination adverse effects, Young Adult, Health Knowledge, Attitudes, Practice, Infertility, Male etiology, Papillomavirus Infections prevention & control, Papillomavirus Vaccines adverse effects, Parents psychology, Patient Acceptance of Health Care, Vaccination psychology
- Abstract
Background: This study sought to determine if parents of males express concerns about vaccine-associated infertility (VAI) with the human papillomavirus (HPV) vaccine and to understand the impact of those concerns., Methods: Parents of sons were surveyed to determine VAI concerns. Logistic regression was used to find if parents worried about VAI had lower knowledge of HPV disease, more concern for side effects, lacked information about vaccination, or had lower intention to vaccinate., Results: In all, 39% of parents were worried about VAI. Parents worried about VAI had similar knowledge of HPV compared with other parents. Parents worried about VAI had twice the odds of agreeing the vaccine may cause side effects and agreeing they did not have enough information compared to their counterparts. Parents worried about VAI less often intended to vaccinate sons than other parents., Conclusions: These findings suggest many parents worry about VAI in sons with HPV vaccine.
- Published
- 2014
- Full Text
- View/download PDF
39. Melanopsin and rod-cone photoreceptors play different roles in mediating pupillary light responses during exposure to continuous light in humans.
- Author
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Gooley JJ, Ho Mien I, St Hilaire MA, Yeo SC, Chua EC, van Reen E, Hanley CJ, Hull JT, Czeisler CA, and Lockley SW
- Subjects
- Adult, Female, Humans, Male, Middle Aged, Pupil physiology, Young Adult, Adaptation, Ocular physiology, Photic Stimulation methods, Reflex, Pupillary physiology, Retinal Cone Photoreceptor Cells physiology, Retinal Rod Photoreceptor Cells physiology, Rod Opsins physiology
- Abstract
In mammals, the pupillary light reflex is mediated by intrinsically photosensitive melanopsin-containing retinal ganglion cells that also receive input from rod-cone photoreceptors. To assess the relative contribution of melanopsin and rod-cone photoreceptors to the pupillary light reflex in humans, we compared pupillary light responses in normally sighted individuals (n = 24) with a blind individual lacking rod-cone function. Here, we show that visual photoreceptors are required for normal pupillary responses to continuous light exposure at low irradiance levels, and for sustained pupillary constriction during exposure to light in the long-wavelength portion of the visual spectrum. In the absence of rod-cone function, pupillomotor responses are slow and sustained, and cannot track intermittent light stimuli, suggesting that rods/cones are required for encoding fast modulations in light intensity. In sighted individuals, pupillary constriction decreased monotonically for at least 30 min during exposure to continuous low-irradiance light, indicating that steady-state pupillary responses are an order of magnitude slower than previously reported. Exposure to low-irradiance intermittent green light (543 nm; 0.1-4 Hz) for 30 min, which was given to activate cone photoreceptors repeatedly, elicited sustained pupillary constriction responses that were more than twice as great compared with exposure to continuous green light. Our findings demonstrate nonredundant roles for rod-cone photoreceptors and melanopsin in mediating pupillary responses to continuous light. Moreover, our results suggest that it might be possible to enhance nonvisual light responses to low-irradiance exposures by using intermittent light to activate cone photoreceptors repeatedly in humans.
- Published
- 2012
- Full Text
- View/download PDF
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