Imperial College London

DrPaulaCunnea

Faculty of MedicineDepartment of Surgery & Cancer

Research Fellow
 
 
 
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Contact

 

+44 (0)20 7594 1548p.cunnea

 
 
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Location

 

Institute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

60 results found

Cunnea P, Fotopoulou C, Ploski J, Trillsch F, Mahner S, Kessler Met al., 2021, Changes in Stem Cell Regulation and Epithelial Organisation during Carcinogenesis and Disease Progression in Gynaecological Malignancies, CANCERS, Vol: 13

Journal article

Lu H, Cunnea P, Nixon K, Rinne N, Aboagye EO, Fotopoulou Cet al., 2021, Discovery of a biomarker candidate for surgical stratification in high-grade serous ovarian cancer, British Journal of Cancer, Vol: 124, Pages: 1286-1293, ISSN: 0007-0920

Background: Maximal effort cytoreductive surgery is associated with improved outcomes in advanced high-grade serous ovarian cancer (HGSOC). However, despite complete gross resection (CGR), there is a percentage of patients who will relapse and die early. The aim of this study is to identify potential candidate biomarkers to help personalise surgical radicality.Methods: 136 advanced HGSOC cases who underwent CGR were identified from three public transcriptomic datasets. Candidate prognostic biomarkers were discovered in this cohort by Cox regression analysis, and further validated by targeted RNA-sequencing in HGSOC cases from Imperial College Healthcare NHS Trust (n = 59), and a public dataset. Gene set enrichment analysis was performed to understand the biological significance of the candidate biomarker.Results: We identified ALG5 as a prognostic biomarker for early tumour progression in advanced HGSOC despite CGR (HR = 2.42, 95% CI (1.57–3.75), p < 0.0001). The prognostic value of this new candidate biomarker was additionally confirmed in two independent datasets (HR = 1.60, 95% CI (1.03–2.49), p = 0.0368; HR = 3.08, 95% CI (1.07–8.81), p = 0.0365). Mechanistically, the oxidative phosphorylation was demonstrated as a potential biological pathway of ALG5-high expression in patients with early relapse (p < 0.001).Conclusion: ALG5 has been identified as an independent prognostic biomarker for poor prognosis in advanced HGSOC patients despite CGR. This sets a promising platform for biomarker combinations and further validations towards future personalised surgical care.

Journal article

Bartl T, Karacs J, Kreuzinger C, Pfaffinger S, Kendler J, Ciocsirescu C, Wolf A, Reinthaller A, Meyer E, Brandstetter M, Postl M, Langthaler E, Braicu E, Vergote I, Cunnea P, Gourley C, Schmitt WD, Cacsire Castillo-Tong D, Christoph Get al., 2021, Tumor Growth Rate Estimates Are Independently Predictive of Therapy Response and Survival in Recurrent High-Grade Serous Ovarian Cancer Patients, CANCERS, Vol: 13

Journal article

Hu Z, Cunnea P, Zhong Z, Lu H, Osagie OI, Campo L, Artibani M, Nixon K, Ploski J, Santana Gonzalez L, Alsaadi A, Wietek N, Damato S, Dhar S, Blagden SP, Yau C, Hester J, Albukhari A, Aboagye EO, Fotopoulou C, Ahmed Aet al., 2021, The Oxford Classic links epithelial-to-mesenchymal transition to immunosuppression in poor prognosis ovarian cancers, Clinical Cancer Research, Vol: 27, Pages: 1570-1579, ISSN: 1078-0432

Purpose: Using RNA sequencing, we recently developed the 52-gene–based Oxford classifier of carcinoma of the ovary (Oxford Classic, OxC) for molecular stratification of serous ovarian cancers (SOCs) based on the molecular profiles of their cell of origin in the fallopian tube epithelium. Here, we developed a 52-gene NanoString panel for the OxC to test the robustness of the classifier.Experimental Design: We measured the expression of the 52 genes in an independent cohort of prospectively collected SOC samples (n = 150) from a homogenous cohort who were treated with maximal debulking surgery and chemotherapy. We performed data mining of published expression profiles of SOCs and validated the classifier results on tissue arrays comprising 137 SOCs.Results: We found evidence of profound nongenetic heterogeneity in SOCs. Approximately 20% of SOCs were classified as epithelial-to-mesenchymal transition–high (EMT-high) tumors, which were associated with poor survival. This was independent of established prognostic factors, such as tumor stage, tumor grade, and residual disease after surgery (HR, 3.3; P = 0.02). Mining expression data of 593 patients revealed a significant association between the EMT scores of tumors and the estimated fraction of alternatively activated macrophages (M2; P < 0.0001), suggesting a mechanistic link between immunosuppression and poor prognosis in EMT-high tumors.Conclusions: The OxC-defined EMT-high SOCs carry particularly poor prognosis independent of established clinical parameters. These tumors are associated with high frequency of immunosuppressive macrophages, suggesting a potential therapeutic target to improve clinical outcome.

Journal article

Periyasamy M, Singh AK, Gemma C, Farzan R, Allsopp RC, Shaw JA, Charmsaz S, Young LS, Cunnea P, Coombes RC, Győrffy B, Buluwela L, Ali Set al., 2021, Induction of APOBEC3B expression by chemotherapy drugs is mediated by DNA-PK-directed activation of NF-κB., Oncogene, Vol: 40, Pages: 1077-1090

The mutagenic APOBEC3B (A3B) cytosine deaminase is frequently over-expressed in cancer and promotes tumour heterogeneity and therapy resistance. Hence, understanding the mechanisms that underlie A3B over-expression is important, especially for developing therapeutic approaches to reducing A3B levels, and consequently limiting cancer mutagenesis. We previously demonstrated that A3B is repressed by p53 and p53 mutation increases A3B expression. Here, we investigate A3B expression upon treatment with chemotherapeutic drugs that activate p53, including 5-fluorouracil, etoposide and cisplatin. Contrary to expectation, these drugs induced A3B expression and concomitant cellular cytosine deaminase activity. A3B induction was p53-independent, as chemotherapy drugs stimulated A3B expression in p53 mutant cells. These drugs commonly activate ATM, ATR and DNA-PKcs. Using specific inhibitors and gene knockdowns, we show that activation of DNA-PKcs and ATM by chemotherapeutic drugs promotes NF-κB activity, with consequent recruitment of NF-κB to the A3B gene promoter to drive A3B expression. Further, we find that A3B knockdown re-sensitises resistant cells to cisplatin, and A3B knockout enhances sensitivity to chemotherapy drugs. Our data highlight a role for A3B in resistance to chemotherapy and indicate that stimulation of A3B expression by activation of DNA repair and NF-κB pathways could promote cancer mutations and expedite chemoresistance.

Journal article

Cunnea P, Curry E, Christie E, Nixon K, Kwok CH, Ploski J, Wulandari R, Bowtell D, Fotopoulou Cet al., 2020, GENOMIC AND FUNCTIONAL CHARACTERISATION OF INTRA-TUMOURAL HETEROGENEITY IN HIGH GRADE SEROUS OVARIAN CANCER, Publisher: BMJ PUBLISHING GROUP, Pages: A98-A99, ISSN: 1048-891X

Conference paper

Ploski J, Nixon K, Demchenko N, Cunnea P, Fotopoulou Cet al., 2020, NOVEL 3D MODEL SYSTEMS TO ASSESS HETEROGENEITY IN RESPONSE TO PLATINUM THERAPY IN HIGH GRADE SEROUS OVARIAN CANCER, Publisher: BMJ PUBLISHING GROUP, Pages: A99-A99, ISSN: 1048-891X

Conference paper

Rinne N, Yuan S, Fotopoulou C, Gabra H, Cunnea Pet al., 2020, TARGETING AKT AND DNA-PK AS A THERAPEUTIC STRATEGY IN PLATINUM RESISTANT HIGH-GRADE SEROUS OVARIAN CANCER, Publisher: BMJ PUBLISHING GROUP, Pages: A62-A62, ISSN: 1048-891X

Conference paper

Periyasamy M, Singh A, Gemma C, Farzan R, Allsopp R, Shaw J, Charmasz S, Young L, Cunnea P, Coombes R, Gyorffy B, Buluwela L, Ali Set al., 2020, Induction of APOBEC3B expression by chemotherapy drugs is mediated by DNA-PK directed activation of NF-κB, Oncogene, Vol: 15 December 2020, Pages: 1077-1090, ISSN: 0950-9232

The mutagenic APOBEC3B (A3B) cytosine deaminase is frequently over-expressed in cancer and promotes tumour heterogeneity and therapy resistance. Hence, understanding the mechanisms that underlie A3B over-expression is important, especially for developing therapeutic approaches to reducing A3B levels, and consequently limiting cancer mutagenesis. We previously demonstrated that A3B is repressed by p53 and p53 mutation increases A3B expression. Here, we investigate A3B expression upon treatment with chemotherapeutic drugs that activate p53, including 5-fluorouracil, etoposide and cisplatin. Contrary to expectation, these drugs induced A3B expression and concomitant cellular cytosine deaminase activity. A3B induction was p53-independent, as chemotherapy drugs stimulated A3B expression in p53 mutant cells. These drugs commonly activate ATM, ATR and DNA-PKcs. Using specific inhibitors and gene knockdowns, we show that activation of DNA-PKcs and ATM by chemotherapeutic drugs promotes NF-kB activity, with consequent recruitment of NF-kB to the A3B gene promoter to drive A3B expression. Further, we find that A3B knockdown re-sensitises resistant cells to cisplatin, and A3B knockout enhances sensitivity to chemotherapy drugs. Our data highlight a role for A3B in resistance to chemotherapy and indicate that stimulation of A3B expression by activation of DNA repair and NF-kB pathways could promote cancer mutations and expedite chemoresistance.

Journal article

Fotopoulou C, Rinne N, Ghirardi V, Cunnea P, Drosou A, Tzovaras D, Giudice MT, Scambia G, Fagotti Aet al., 2020, Value of pre-existent bacterial colonization in patients with advanced/relapsed ovarian neoplasms undergoing cytoreductive surgery: a multicenter observational study (BONSAI), INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, Vol: 30, Pages: 1562-1568, ISSN: 1048-891X

Journal article

Johnson SC, Chakraborty S, Drosou A, Cunnea P, Tzovaras D, Nixon K, Zawieja DC, Muthuchamy M, Fotopoulou C, Moore JEet al., 2020, Inflammatory state of lymphatic vessels and miRNA profiles associated with relapse in ovarian cancer patients, PLoS One, Vol: 15, Pages: 1-23, ISSN: 1932-6203

Lymphogenic spread is associated with poor prognosis in epithelial ovarian cancer (EOC), yet little is known regarding roles of non-peri-tumoural lymphatic vessels (LVs) outside the tumour microenvironment that may impact relapse. The aim of this feasibility study was to assess whether inflammatory status of the LVs and/or changes in the miRNA profile of the LVs have potential prognostic and predictive value for overall outcome and risk of relapse. Samples of macroscopically normal human lymph LVs (n = 10) were isolated from the external iliac vessels draining the pelvic region of patients undergoing debulking surgery. This was followed by quantification of the inflammatory state (low, medium and high) and presence of cancer-infiltration of each LV using immunohistochemistry. LV miRNA expression profiling was also performed, and analysed in the context of high versus low inflammation, and cancer-infiltrated versus non-cancer-infiltrated. Results were correlated with clinical outcome data including relapse with an average follow-up time of 13.3 months. The presence of a high degree of inflammation correlated significantly with patient relapse (p = 0.033). Cancer-infiltrated LVs showed a moderate but non-significant association with relapse (p = 0.07). Differential miRNA profiles were identified in cancer-infiltrated LVs and those with high versus low inflammation. In particular, several members of the let-7 family were consistently down-regulated in highly inflamed LVs (>1.8-fold, p<0.05) compared to the less inflamed ones. Down-regulation of the let-7 family appears to be associated with inflammation, but whether inflammation contributes to or is an effect of cancer-infiltration requires further investigation.

Journal article

Cunnea P, Curry E, Nixon K, Wulandari R, Thol K, Kwok CH, Ploski J, McNeish I, Christie E, Bowtell D, Fotopoulou Cet al., 2020, Phenotypic and genomic characterization of intratumoral heterogeneity in high-grade serous ovarian cancer., AACR Special Conference on Advances in Ovarian Cancer Research, Publisher: AMER ASSOC CANCER RESEARCH, Pages: 42-42, ISSN: 1078-0432

Conference paper

Sabini C, Sorbi F, Cunnea P, Fotopoulou Cet al., 2020, Ovarian cancer stem cells: ready for prime time?, ARCHIVES OF GYNECOLOGY AND OBSTETRICS, Vol: 301, Pages: 895-899, ISSN: 0932-0067

Journal article

Rinne N, Curry E, Fotopoulou C, Gabra H, Cunnea Pet al., 2019, TARGETING AKT AND DNA-PK AS A THERAPEUTIC STRATEGY IN PLATINUM RESISTANT HIGH-GRADE SEROUS OVARIAN CANCER, Publisher: BMJ PUBLISHING GROUP, Pages: A512-A513, ISSN: 1048-891X

Conference paper

Nixon K, Curry E, Wulandari R, Morera-Albert C, Cunnea P, Fotopoulou Cet al., 2019, USE OF 3D ORGANOTYPIC MODELS TO ASSESS HETEROGENEITY IN RESPONSE TO PLATINUM THERAPY IN HIGH GRADE SEROUS OVARIAN CANCER, Publisher: BMJ PUBLISHING GROUP, Pages: A145-A145, ISSN: 1048-891X

Conference paper

Cunnea P, Curry E, Nixon K, Thol K, Wulandari R, Bowtell D, McNeish I, Fotopoulou Cet al., 2019, MOLECULAR AND PHENOTYPIC CHARACTERISATION OF INTRA-TUMOURAL HETEROGENEITY IN HIGH GRADE SEROUS OVARIAN CANCER, Publisher: BMJ PUBLISHING GROUP, Pages: A50-A51, ISSN: 1048-891X

Conference paper

Hall M, Savvatis K, Nixon K, Kyrgiou M, Hariharan K, Padwick M, Owens O, Cunnea P, Campbell J, Farthing A, Stumpfle R, Vazquez I, Watson N, Krell J, Gabra H, Rustin G, Fotopoulou Cet al., 2019, Maximal-effort cytoreductive surgery for ovarian cancer patients with a high tumor burden: variations in practice and impact on outcome, Annals of Surgical Oncology, Vol: 26, Pages: 2943-2951, ISSN: 1068-9265

BackgroundThis study aimed to compare the outcomes of two distinct patient populations treated within two neighboring UK cancer centers (A and B) for advanced epithelial ovarian cancer (EOC).MethodsA retrospective analysis of all new stages 3 and 4 EOC patients treated between January 2013 and December 2014 was performed. The Mayo Clinic surgical complexity score (SCS) was applied. Cox regression analysis identified the impact of treatment methods on survival.ResultsThe study identified 249 patients (127 at center A and 122 in centre B) without significant differences in International Federation of Gynecology and Obstetrics (FIGO) stage (FIGO 4, 29.7% at centers A and B), Eastern Cooperative Oncology Group (ECOG) performance status (ECOG < 2, 89.9% at centers A and B), or histology (serous type in 84.1% at centers A and B). The patients at center A were more likely to undergo surgery (87% vs 59.8%; p < 0.001). The types of chemotherapy and the patients receiving palliative treatment alone were equivalent between the two centers (3.6%). The median SCS was significantly higher at center A (9 vs 2; p < 0.001) with greater tumor burden (9 vs 6 abdominal fields involved; p < 0.001), longer median operation times (285 vs 155 min; p < 0.001), and longer hospital stays (9 vs 6 days; p < 0.001), but surgical morbidity and mortality were equivalent. The independent predictors of reduced overall survival (OS) were non-serous histology (hazard ratio [HR], 1.6; 95% confidence interval [CI] 1.04–2.61), ECOG higher than 2 (HR, 1.9; 95% CI 1.15–3.13), and palliation alone (HR, 3.43; 95% CI 1.51–7.81). Cytoreduction, of any timing, had an independent protective impact on OS compared with chemotherapy alone (HR, 0.31 for interval surgery and 0.39 for primary surgery), even after adjustment for other prognostic factors.ConclusionsIncorporating surgery into the initia

Journal article

Nixon K, Wulandari R, Curry E, Rama N, Bowtell D, Cunnea P, Fotopoulou Cet al., 2019, Describing intratumoural heterogeneity in high-grade serous ovarian cancer, Publisher: WILEY, Pages: 87-88, ISSN: 1470-0328

Conference paper

Lu H, Arshad M, Thornton A, Avesani G, Cunnea P, Curry E, Kanavati F, Liang J, Nixon K, Williams S, Hassan M, Bowtell D, Gabra H, Fotopoulou C, Rockall A, Aboagye Eet al., 2019, A mathematical descriptor of tumour mesoscopic structure from computed tomography images annotates prognostic and molecular phenotypes of epithelial ovarian cancer, Publisher: WILEY, Pages: 89-89, ISSN: 1470-0328

Conference paper

Rinne N, Curry E, Fotopoulou C, Gabra H, Cunnea Pet al., 2019, Targeting AKT and DNA-PK as a therapeutic strategy in platinum-resistant high-grade serous ovarian cancer, Publisher: WILEY, Pages: 88-89, ISSN: 1470-0328

Conference paper

Lu H, Arshad M, Thornton A, Avesani G, Cunnea P, Curry E, Kanavati F, Nixon K, Williams ST, Ali Hassan M, Bowtell DDL, Gabra H, Fotopoulou C, Rockall A, Aboagye Eet al., 2019, A mathematical-descriptor of tumor-mesoscopic-structure from computed-tomography images annotates prognostic and molecular-phenotypes of epithelial ovarian cancer, Nature Communications, Vol: 10, ISSN: 2041-1723

The five-year survival rate of epithelial ovarian cancer (EOC) is approximately 35–40% despite maximal treatment efforts, highlighting a need for stratification biomarkers for personalized treatment. Here we extract 657 quantitative mathematical descriptors from the preoperative CT images of 364 EOC patients at their initial presentation. Using machine learning, we derive a non-invasive summary-statistic of the primary ovarian tumor based on 4 descriptors, which we name “Radiomic Prognostic Vector” (RPV). RPV reliably identifies the 5% of patients with median overall survival less than 2 years, significantly improves established prognostic methods, and is validated in two independent, multi-center cohorts. Furthermore, genetic, transcriptomic and proteomic analysis from two independent datasets elucidate that stromal phenotype and DNA damage response pathways are activated in RPV-stratified tumors. RPV and its associated analysis platform could be exploited to guide personalized therapy of EOC and is potentially transferrable to other cancer types.

Journal article

Kreuzinger C, von der Decken I, Wolf A, Gamperl M, Koller J, Karacs J, Pfaffinger S, Bartl T, Reinthaller A, Grimm C, Singer CF, Braicu EI, Cunnea P, Gourley C, Smeets D, Boeckx B, Lambrechts D, Perco P, Horvat R, Berns EMJJ, Castillo-Tong DCet al., 2019, Patient-derived cell line models revealed therapeutic targets and molecular mechanisms underlying disease progression of high grade serous ovarian cancer, CANCER LETTERS, Vol: 459, Pages: 1-12, ISSN: 0304-3835

Journal article

Cunnea P, Gorgy T, Petkos K, Gowers S, Lu H, Morera C, Wu W, Lawton P, Nixon K, Leong C, Sorbi F, Domenici L, Paterson A, Curry E, Gabra H, Boutelle M, Drakakis E, Fotopoulou Cet al., 2018, Clinical value of bioelectrical properties of cancerous tissue in advanced epithelial ovarian cancer patients, Scientific Reports, Vol: 8, Pages: 1-12, ISSN: 2045-2322

Currently, there are no valid pre-operatively established biomarkers or algorithms that can accurately predict surgical and clinical outcome for patients with advanced epithelial ovarian cancer (EOC). In this study, we suggest that profiling of tumour parameters such as bioelectrical-potential and metabolites, detectable by electronic sensors, could facilitate the future development of devices to better monitor disease and predict surgical and treatment outcomes. Biopotential was recorded, using a potentiometric measurement system, in ex vivo paired non-cancerous and cancerous omental tissues from advanced stage EOC (n = 36), and lysates collected for metabolite measurement by microdialysis. Consistently different biopotential values were detected in cancerous tissue versus non-cancerous tissue across all cases (p < 0.001). High tumour biopotential levels correlated with advanced tumour stage (p = 0.048) and tumour load, and negatively correlated with stroma. Within our EOC cohort and specifically the high-grade serous subtype, low biopotential levels associated with poorer progression-free survival (p = 0.0179, p = 0.0143 respectively). Changes in biopotential levels significantly correlated with common apoptosis related pathways. Lactate and glucose levels measured in paired tissues showed significantly higher lactate/glucose ratio in tissues with low biopotential (p < 0.01, n = 12). Our study proposes the feasibility of biopotential and metabolite monitoring as a biomarker modality profiling EOC to predict surgical and clinical outcomes.

Journal article

Antony J, Zanini E, Kelly Z, Tan TZ, Karali E, Alomary M, Jung Y, Nixon K, Cunnea P, Fotopoulou C, Paterson A, Roy-Nawathe S, Mills GB, Huang RY-J, Thiery JP, Gabra H, Recchi Cet al., 2018, The tumour suppressor OPCML promotes AXL inactivation by the phosphatase PTPRG in ovarian cancer, EMBO Reports, Vol: 19, ISSN: 1469-221X

In ovarian cancer, the prometastatic RTK AXL promotes motility, invasion and poor prognosis. Here, we show that reduced survival caused by AXL overexpression can be mitigated by the expression of the GPI-anchored tumour suppressor OPCML Further, we demonstrate that AXL directly interacts with OPCML, preferentially so when AXL is activated by its ligand Gas6. As a consequence, AXL accumulates in cholesterol-rich lipid domains, where OPCML resides. Here, phospho-AXL is brought in proximity to the lipid domain-restricted phosphatase PTPRG, which de-phosphorylates the RTK/ligand complex. This prevents AXL-mediated transactivation of other RTKs (cMET and EGFR), thereby inhibiting sustained phospho-ERK signalling, induction of the EMT transcription factor Slug, cell migration and invasion. From a translational perspective, we show that OPCML enhances the effect of the phase II AXL inhibitor R428 in vitro and in vivo We therefore identify a novel mechanism by which two spatially restricted tumour suppressors, OPCML and PTPRG, coordinate to repress AXL-dependent oncogenic signalling.

Journal article

Boutelle MG, Gowers SAN, Hamaoui K, Cunnea P, Anastasova-Ivanova S, Curto VF, Vadgama P, Yang G-Z, Papalois V, Drakakis EM, Weber SG, Boutelle MGet al., 2018, High temporal resolution delayed analysis of clinical microdialysate streams, Analyst, Vol: 143, Pages: 715-724, ISSN: 1364-5528

This paper presents the use of tubing to store clinical microdialysis samples for delayed analysis with high temporal resolution, offering an alternative to traditional discrete offline microdialysis sampling. Samples stored in this way were found to be stable for up to 72 days at −80 °C. Examples of how this methodology can be applied to glucose and lactate measurement in a wide range of in vivo monitoring experiments are presented. This paper presents a general model, which allows for an informed choice of tubing parameters for a given storage time and flow rate avoiding high back pressure, which would otherwise cause the microdialysis probe to leak, while maximising temporal resolution.

Journal article

Nixon K, Cunnea P, Wulandari R, Curry E, Albert-Morera C, Rama N, Bowtell D, Gabra H, Stronach E, Fotopoulou Cet al., 2017, DESCRIBING INTRA-TUMOURAL HETEROGENEITY IN HIGH GRADE SEROUS OVARIAN CANCER, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 1613-1613, ISSN: 1048-891X

Conference paper

Lu H, Fotopoulou C, Rockall A, Curry E, Arshad M, Thornton A, Cunnea P, Gabra H, Aboagye Eet al., 2017, PRE-OPERATIVE RADIOMIC MODELS ANNOTATE EPITHELIAL OVARIAN CANCER PROGNOSTIC PHENOTYPES, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 1490-1490, ISSN: 1048-891X

Conference paper

Lu H, Fotopoulou C, Rockall A, Curry E, Arshad M, Thornton A, Cunnea P, Gabra H, Aboagye Eet al., 2017, PRE-OPERATIVE RADIOMIC MODELS ANNOTATE EPITHELIAL OVARIAN CANCER PROGNOSTIC PHENOTYPES, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 502-502, ISSN: 1048-891X

Conference paper

Nixon K, Cunnea P, Wulandari R, Curry E, Albert-Morera C, Rama N, Bowtell D, Gabra H, Stronach E, Fotopoulou Cet al., 2017, DESCRIBING INTRA-TUMOURAL HETEROGENEITY IN HIGH GRADE SEROUS OVARIAN CANCER, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 516-516, ISSN: 1048-891X

Conference paper

Athanasiou D, Edgar LT, Jafarnejad M, Nixon K, Duarte D, Hawkins ED, Jamalian S, Cunnea P, Lo Celso C, Kobayashi S, Fotopoulou C, Moore JEet al., 2017, The passive biomechanics of human pelvic collecting lymphatic vessels, PLOS One, Vol: 12, ISSN: 1932-6203

The lymphatic system has a major significance in the metastatic pathways in women’s cancers. Lymphatic pumping depends on both extrinsic and intrinsic mechanisms, and the mechanical behavior of lymphatic vessels regulates the function of the system. However, data on the mechanical properties and function of human lymphatics are lacking. Our aim is to characterize, for the first time, the passive biomechanical behavior of human collecting lymphatic vessels removed at pelvic lymph node dissection during primary debulking surgeries for epithelial ovarian cancer. Isolated vessels were cannulated and then pressurized at varying levels of applied axial stretch in a calcium-free Krebs buffer. Pressurized vessels were then imaged using multi-photon microscopy for collagen-elastin structural composition and fiber orientation. Both pressure-diameter and force-elongation responses were highly nonlinear, and axial stretching of the vessel served to decrease diameter at constant pressure. Pressure-diameter behavior for the human vessels is very similar to data from rat mesenteric vessels, though the human vessels were approximately 10× larger than those from rats. Multiphoton microscopy revealed the vessels to be composed of an inner layer of elastin with an outer layer of aligned collagen fibers. This is the first study that successfully described the passive biomechanical response and composition of human lymphatic vessels in patients with ovarian cancer. Future work should expand on this knowledge base with investigations of vessels from other anatomical locations, contractile behavior, and the implications on metastatic cell transport.

Journal article

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