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Article: Organ-on-a-Chip and Microfluidic Platforms for Oncology in the UK.

Nolan, Joanne / Pearce, Oliver M T / Screen, Hazel R C / Knight, Martin M / Verbruggen, Stefaan W

2023 Volume 15, Issue 3

Abstract: Organ-on-chip systems are capable of replicating complex tissue structures and physiological phenomena. The fine control of biochemical and biomechanical cues within these microphysiological systems provides opportunities for cancer researchers to build ... ...

Abstract	Organ-on-chip systems are capable of replicating complex tissue structures and physiological phenomena. The fine control of biochemical and biomechanical cues within these microphysiological systems provides opportunities for cancer researchers to build complex models of the tumour microenvironment. Interest in applying organ chips to investigate mechanisms such as metastatsis and to test therapeutics has grown rapidly, and this review draws together the published research using these microfluidic platforms to study cancer. We focus on both in-house systems and commercial platforms being used in the UK for fundamental discovery science and therapeutics testing. We cover the wide variety of cancers being investigated, ranging from common carcinomas to rare sarcomas, as well as secondary cancers. We also cover the broad sweep of different matrix microenvironments, physiological mechanical stimuli and immunological effects being replicated in these models. We examine microfluidic models specifically, rather than organoids or complex tissue or cell co-cultures, which have been reviewed elsewhere. However, there is increasing interest in incorporating organoids, spheroids and other tissue cultures into microfluidic organ chips and this overlap is included. Our review includes a commentary on cancer organ-chip models being developed and used in the UK, including work conducted by members of the UK Organ-on-a-Chip Technologies Network. We conclude with a reflection on the likely future of this rapidly expanding field of oncological research.
Language	English
Publishing date	2023-01-19
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15030635
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Collagen-I influences the post-translational regulation, binding partners and role of Annexin A2 in breast cancer progression.

Mahdi, Amira F / Nolan, Joanne / O'Connor, Ruth Í / Lowery, Aoife J / Allardyce, Joanna M / Kiely, Patrick A / McGourty, Kieran

Frontiers in oncology

2023 Volume 13, Page(s) 1270436

Abstract: Introduction: The extracellular matrix (ECM) has been heavily implicated in the development and progression of cancer. We have previously shown that Annexin A2 is integral in the migration and invasion of breast cancer cells and in the clinical ... ...

Abstract	Introduction: The extracellular matrix (ECM) has been heavily implicated in the development and progression of cancer. We have previously shown that Annexin A2 is integral in the migration and invasion of breast cancer cells and in the clinical progression of ER-negative breast cancer, processes which are highly influenced by the surrounding tumor microenvironment and ECM. Methods: We investigated how modulations of the ECM may affect the role of Annexin A2 in MDA-MB-231 breast cancer cells using western blotting, immunofluorescent confocal microscopy and immuno-precipitation mass spectrometry techniques. Results: We have shown that the presence of collagen-I, the main constituent of the ECM, increases the post-translational phosphorylation of Annexin A2 and subsequently causes the translocation of Annexin A2 to the extracellular surface. In the presence of collagen-I, we identified fibronectin as a novel interactor of Annexin A2, using mass spectrometry analysis. We then demonstrated that reducing Annexin A2 expression decreases the degradation of fibronectin by cancer cells and this effect on fibronectin turnover is increased according to collagen-I abundance. Discussion: Our results suggest that Annexin A2's role in promoting cancer progression is mediated by collagen-I and Annexin A2 maybe a therapeutic target in the bi-directional cross-talk between cancer cells and ECM remodeling that supports metastatic cancer progression.
Language	English
Publishing date	2023-10-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2023.1270436
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Article ; Online: A Novel Primary Cilium-Mediated Mechanism Through which Osteocytes Regulate Metastatic Behavior of Both Breast and Prostate Cancer Cells.

Verbruggen, Stefaan W / Nolan, Joanne / Duffy, Michael P / Pearce, Oliver M T / Jacobs, Christopher R / Knight, Martin M

Advanced science (Weinheim, Baden-Wurttemberg, Germany)

2023 Volume 11, Issue 2, Page(s) e2305842

Abstract: Bone metastases are a common cause of suffering in breast and prostate cancer patients, however, the interaction between bone cells and cancer cells is poorly understood. Using a series of co-culture, conditioned media, human cancer spheroid, and organ- ... ...

Abstract	Bone metastases are a common cause of suffering in breast and prostate cancer patients, however, the interaction between bone cells and cancer cells is poorly understood. Using a series of co-culture, conditioned media, human cancer spheroid, and organ-on-a-chip experiments, this study reveals that osteocytes suppress cancer cell proliferation and increase migration via tumor necrosis factor alpha (TNF-α) secretion. This action is regulated by osteocyte primary cilia and associated intraflagellar transport protein 88 (IFT88). Furthermore, it shows that cancer cells block this mechanism by secreting transforming growth factor beta (TGF-β), which disrupts osteocyte cilia and IFT88 gene expression. This bi-directional crosstalk signaling between osteocytes and cancer cells is common to both breast and prostate cancer. This study also proposes that osteocyte inhibition of cancer cell proliferation decreases as cancer cells increase, producing more TGF-β. Hence, a positive feedback loop develops accelerating metastatic tumor growth. These findings demonstrate the importance of cancer cell-osteocyte signaling in regulating breast and prostate bone metastases and support the development of therapies targeting this pathway.
MeSH term(s)	Male ; Humans ; Osteocytes/metabolism ; Cilia ; Prostate ; Prostatic Neoplasms ; Bone Neoplasms/metabolism ; Transforming Growth Factor beta/metabolism
Chemical Substances	Transforming Growth Factor beta
Language	English
Publishing date	2023-11-15
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2808093-2
ISSN	2198-3844 ; 2198-3844
ISSN (online)	2198-3844
ISSN	2198-3844
DOI	10.1002/advs.202305842
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Article ; Online: Collagen and fibronectin promote an aggressive cancer phenotype in breast cancer cells but drive autonomous gene expression patterns.

Nolan, Joanne / Mahdi, Amira F / Dunne, Colum P / Kiely, Patrick A

Gene

2020 Volume 761, Page(s) 145024

Abstract: Understanding how various pathologies of breast cancer respond to their environment may be imperative in the creation of novel therapeutic targets. Central to the organisation and behaviour of cells within the tumour microenvironment is the extracellular ...

Abstract	Understanding how various pathologies of breast cancer respond to their environment may be imperative in the creation of novel therapeutic targets. Central to the organisation and behaviour of cells within the tumour microenvironment is the extracellular matrix (ECM), a meshwork of fibrous proteins and glycoproteins that directly influences cell behaviour and the bioavailability of signalling molecules. Our appreciation on how the composition of the ECM can influence cancer behaviour has evolved significantly and although we are highly cognisant of the dramatic impact the ECM can have on cancer cell behaviour, we continue to neglect this during diagnosis and treatment. In the following study, we aimed to identify how three breast cancer cell lines respond functionally and genetically to common components of the ECM. Using real time and end point assays we have identified similar patterns of behaviour among the three breast cancer cell lines in response to commonly found ECM components of the breast. Using a selected gene panel, we have been able to identify cell line specific changes in gene differentiation when breast cancer cells are in contact with these elements. Although the response of our cells to these elements differ at the genetic level, their functional responses are consistent. This work adds to the growing arguments that highlight a need for histologically assessing ECM composition of breast tumours. In particular monitoring of fibrous protein deposition at the site of malignancy could provide critical information during clinical assessment influencing disease prognosis and treatment decisions for breast cancer patients.
MeSH term(s)	Breast/pathology ; Breast Neoplasms/genetics ; Cell Line, Tumor ; Collagen/genetics ; Collagen/metabolism ; Collagen Type I/genetics ; Extracellular Matrix/metabolism ; Extracellular Matrix Proteins/genetics ; Female ; Fibronectins/genetics ; Fibronectins/metabolism ; Gene Expression Profiling/methods ; Gene Expression Regulation, Neoplastic/genetics ; Genotype ; Glycoproteins/genetics ; Humans ; Phenotype ; Prognosis ; Signal Transduction ; Tumor Microenvironment
Chemical Substances	Collagen Type I ; Extracellular Matrix Proteins ; FN1 protein, human ; Fibronectins ; Glycoproteins ; Collagen (9007-34-5)
Language	English
Publishing date	2020-08-02
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	391792-7
ISSN	1879-0038 ; 0378-1119
ISSN (online)	1879-0038
ISSN	0378-1119
DOI	10.1016/j.gene.2020.145024
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Article: Collagen and fibronectin promote an aggressive cancer phenotype in breast cancer cells but drive autonomous gene expression patterns

Nolan, Joanne / Mahdi, Amira F / Dunne, Colum P / Kiely, Patrick A

Gene. 2020 Nov. 30, v. 761

2020

Abstract	Understanding how various pathologies of breast cancer respond to their environment may be imperative in the creation of novel therapeutic targets. Central to the organisation and behaviour of cells within the tumour microenvironment is the extracellular matrix (ECM), a meshwork of fibrous proteins and glycoproteins that directly influences cell behaviour and the bioavailability of signalling molecules. Our appreciation on how the composition of the ECM can influence cancer behaviour has evolved significantly and although we are highly cognisant of the dramatic impact the ECM can have on cancer cell behaviour, we continue to neglect this during diagnosis and treatment. In the following study, we aimed to identify how three breast cancer cell lines respond functionally and genetically to common components of the ECM. Using real time and end point assays we have identified similar patterns of behaviour among the three breast cancer cell lines in response to commonly found ECM components of the breast. Using a selected gene panel, we have been able to identify cell line specific changes in gene differentiation when breast cancer cells are in contact with these elements. Although the response of our cells to these elements differ at the genetic level, their functional responses are consistent. This work adds to the growing arguments that highlight a need for histologically assessing ECM composition of breast tumours. In particular monitoring of fibrous protein deposition at the site of malignancy could provide critical information during clinical assessment influencing disease prognosis and treatment decisions for breast cancer patients.
Keywords	assays ; behavior ; bioavailability ; breast neoplasms ; breasts ; cell lines ; chemical elements ; collagen ; environment ; extracellular matrix ; fibronectins ; gene expression regulation ; genes ; glycoproteins ; information ; monitoring ; neoplasm cells ; patients ; phenotype ; prognosis ; protein deposition ; therapeutics
Language	English
Dates of publication	2020-1130
Publishing place	Elsevier B.V.
Document type	Article
Note	NAL-light
ZDB-ID	391792-7
ISSN	1879-0038 ; 0378-1119
ISSN (online)	1879-0038
ISSN	0378-1119
DOI	10.1016/j.gene.2020.145024
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Article ; Online: Proposed hypothesis and rationale for association between mastitis and breast cancer.

Nolan, Joanne / Dunne, Suzanne S / Mustafa, Wed / Sivananthan, Laxsanaa / Kiely, Patrick A / Dunne, Colum P

Medical hypotheses

2020 Volume 144, Page(s) 110057

Abstract: Breast cancer is amongst the most common forms of cancer, is predominantly a woman's illness, and is the most frequently reported invasive cancer in women worldwide (Bray et al., 2018). Varying risk factors have been identified, including genetics, ... ...

Abstract	Breast cancer is amongst the most common forms of cancer, is predominantly a woman's illness, and is the most frequently reported invasive cancer in women worldwide (Bray et al., 2018). Varying risk factors have been identified, including genetics, family history, lifestyle, age and the use of hormone replacement therapy. Mastitis, also predominantly a woman's illness, is an inflammatory condition of the breast that, despite being an inflammation-related condition, is not currently considered a risk factor for breast cancer. This appears counterintuitive as epidemiological studies have identified chronic inflammation as a contributor to cancer risk, for example in gastric, oesophageal and colon cancers (Lin et al., 2016; Qadri et al., 2014; Principe et al., 2017). Previous reports have focused on women hospitalised for mastitis, and most commonly on puerperal mastitis, perhaps underestimating the relationship between breast cancer and non-lactational mastitis. Our hypothesis, based on systematic review, suggests that a longitudinal study of this disease, affecting women predominantly, is warranted.
MeSH term(s)	Breast Neoplasms ; Escherichia coli Infections ; Female ; Humans ; Longitudinal Studies ; Mastitis ; Risk Factors
Language	English
Publishing date	2020-06-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	193145-3
ISSN	1532-2777 ; 0306-9877
ISSN (online)	1532-2777
ISSN	0306-9877
DOI	10.1016/j.mehy.2020.110057
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Article: Mechanical Stimulation Modulates Osteocyte Regulation of Cancer Cell Phenotype.

Verbruggen, Stefaan W / Thompson, Clare L / Duffy, Michael P / Lunetto, Sophia / Nolan, Joanne / Pearce, Oliver M T / Jacobs, Christopher R / Knight, Martin M

Cancers

2021 Volume 13, Issue 12

Abstract: Breast and prostate cancers preferentially metastasise to bone tissue, with metastatic lesions forming in the skeletons of most patients. On arriving in bone tissue, disseminated tumour cells enter a mechanical microenvironment that is substantially ... ...

Abstract	Breast and prostate cancers preferentially metastasise to bone tissue, with metastatic lesions forming in the skeletons of most patients. On arriving in bone tissue, disseminated tumour cells enter a mechanical microenvironment that is substantially different to that of the primary tumour and is largely regulated by bone cells. Osteocytes, the most ubiquitous bone cell type, orchestrate healthy bone remodelling in response to physical exercise. However, the effects of mechanical loading of osteocytes on cancer cell behaviour is still poorly understood. The aim of this study was to characterise the effects of osteocyte mechanical stimulation on the behaviour of breast and prostate cancer cells. To replicate an osteocyte-controlled environment, this study treated breast (MDA-MB-231 and MCF-7) and prostate (PC-3 and LNCaP) cancer cell lines with conditioned media from MLO-Y4 osteocyte-like cells exposed to mechanical stimulation in the form of fluid shear stress. We found that osteocyte paracrine signalling acted to inhibit metastatic breast and prostate tumour growth, characterised by reduced proliferation and invasion and increased migration. In breast cancer cells, these effects were largely reversed by mechanical stimulation of osteocytes. In contrast, conditioned media from mechanically stimulated osteocytes had no effect on prostate cancer cells. To further investigate these interactions, we developed a microfluidic organ-chip model using the Emulate platform. This new organ-chip model enabled analysis of cancer cell migration, proliferation and invasion in the presence of mechanical stimulation of osteocytes by fluid shear stress, resulting in increased invasion of breast and prostate cancer cells. These findings demonstrate the importance of osteocytes and mechanical loading in regulating cancer cell behaviour and the need to incorporate these factors into predictive in vitro models of bone metastasis.
Language	English
Publishing date	2021-06-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13122906
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Article ; Online: Expression of Annexin A2 Promotes Cancer Progression in Estrogen Receptor Negative Breast Cancers.

Mahdi, Amira F / Malacrida, Beatrice / Nolan, Joanne / McCumiskey, Mary E / Merrigan, Anne B / Lal, Ashish / Tormey, Shona / Lowery, Aoife J / McGourty, Kieran / Kiely, Patrick A

Cells

2020 Volume 9, Issue 7

Abstract: When breast cancer progresses to a metastatic stage, survival rates decline rapidly and it is considered incurable. Thus, deciphering the critical mechanisms of metastasis is of vital importance to develop new treatment options. We hypothesize that ... ...

Abstract	When breast cancer progresses to a metastatic stage, survival rates decline rapidly and it is considered incurable. Thus, deciphering the critical mechanisms of metastasis is of vital importance to develop new treatment options. We hypothesize that studying the proteins that are newly synthesized during the metastatic processes of migration and invasion will greatly enhance our understanding of breast cancer progression. We conducted a mass spectrometry screen following bioorthogonal noncanonical amino acid tagging to elucidate changes in the nascent proteome that occur during epidermal growth factor stimulation in migrating and invading cells. Annexin A2 was identified in this screen and subsequent examination of breast cancer cell lines revealed that Annexin A2 is specifically upregulated in estrogen receptor negative (ER-) cell lines. Furthermore, siRNA knockdown showed that Annexin A2 expression promotes the proliferation, wound healing and directional migration of breast cancer cells. In patients, Annexin A2 expression is increased in ER- breast cancer subtypes. Additionally, high Annexin A2 expression confers a higher probability of distant metastasis specifically for ER- patients. This work establishes a pivotal role of Annexin A2 in breast cancer progression and identifies Annexin A2 as a potential therapeutic target for the more aggressive and harder to treat ER- subtype.
MeSH term(s)	Annexin A2/genetics ; Annexin A2/metabolism ; Blotting, Western ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Line, Tumor ; Cell Movement/genetics ; Cell Movement/physiology ; Cell Proliferation/genetics ; Cell Proliferation/physiology ; Electrophoresis, Polyacrylamide Gel ; Female ; Humans ; Immunoprecipitation ; MCF-7 Cells ; Mass Spectrometry ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; Receptors, Estrogen/genetics ; Receptors, Estrogen/metabolism
Chemical Substances	Annexin A2 ; Carrier Proteins ; RNA, Small Interfering ; Receptors, Estrogen ; estrophilin
Language	English
Publishing date	2020-06-30
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells9071582
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Article: Clinical nurses' knowledge of evidence-based practice: constructing a framework to evaluate a multifaceted intervention for implementing EBP.

Mott, Bernice / Nolan, Joanne / Zarb, Nadia / Arnison, Vanessa / Chan, Roxan / Codner, Tracey / Casey, Therese / Jenkins, Bronwyn / Ulrych, Georgiana / Blackburn, Christine / Glanfield, Linda / Halcomb, Elizabeth / Davidson, Patricia M

Contemporary nurse

2005 Volume 19, Issue 1-2, Page(s) 96–104

Abstract: Critical reflection upon nursing practice is pivotal in achieving optimal patient outcomes. Implicit in this statement is knowledge about and an understanding of the implementation of evidence-based practice (EBP). This study sought to evaluate baseline ... ...

Abstract	Critical reflection upon nursing practice is pivotal in achieving optimal patient outcomes. Implicit in this statement is knowledge about and an understanding of the implementation of evidence-based practice (EBP). This study sought to evaluate baseline knowledge in order to assess and inform a multifaceted intervention to promote EBP in a multi-site facility in Western Sydney, Australia. On two consecutive days in February 2003, a convenience sample of 229 nurses were surveyed using a five-item, investigator developed, written survey tool. Data were analysed using descriptive statistics. Although the majority of respondents (n = 143: 62%) stated that they were aware of EBP, a considerable number (n = 86: 38%) stated they had not previously heard of the term. Of concern, 43% (n = 99) of respondents were unable to identify a source of information and resources about EBP. The results of this observational, descriptive survey underscore the importance of ongoing strategic interventions to improve knowledge, access and implementation of EBP amongst clinical nurses. This study also provides baseline data upon which to evaluate local interventions to promote knowledge of EBP amongst clinicians.
MeSH term(s)	Attitude of Health Personnel ; Clinical Competence/standards ; Diffusion of Innovation ; Education, Nursing, Continuing/organization & administration ; Educational Measurement ; Evidence-Based Medicine/education ; Health Knowledge, Attitudes, Practice ; Humans ; Information Dissemination/methods ; Information Storage and Retrieval/methods ; Models, Educational ; Models, Nursing ; Needs Assessment ; New South Wales ; Nursing Education Research ; Nursing Methodology Research ; Nursing Staff, Hospital/education ; Nursing Staff, Hospital/psychology ; Philosophy, Nursing ; Program Development ; Surveys and Questionnaires
Language	English
Publishing date	2005-09-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	1491361-6
ISSN	1037-6178
ISSN	1037-6178
DOI	10.5172/conu.19.1-2.96
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