
Eleni ManiatiQueen Mary University of London | QMUL · Barts Cancer Institute
Eleni Maniati
PhD
About
80
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Introduction
Publications
Publications (80)
Immune checkpoint inhibitors (ICIs) are extremely effective in a subgroup of mismatch repair-deficient (MMRd) cancers, but ~50% remain resistant to treatment. We have shown for the first time that this may be due to the differential regulation of factors linked to response to ICIs upon loss of the different MMR genes. Here, we show that increased P...
Single-cell RNA sequencing (scRNAseq) of tumour-infiltrating immune cells in high-grade serous ovarian cancer (HGSOC) omental biopsies reveals potential targets that could enhance response to neo-adjuvant chemotherapy (NACT). Analysis of 64,097 cells identifies NACT-induced overexpression of stabilin-1 (clever-1) on macrophages and FOXP3 in Tregs t...
In vitro preclinical testing of chimeric antigen receptor (CAR) T cells is mostly carried out in monolayer cell cultures. However, alternative strategies are needed to take into account the complexity and the effects of the tumor microenvironment. Here, we describe the modulation of CAR T-cell activity by malignant cells and fibroblasts in human th...
Despite the initial response to chemotherapy, most high-grade serous ovarian cancer (HGSOC) patients will suffer disease relapse within two years of diagnosis with no currently successful immunotherapy options.We performed single-cell RNA sequencing (scRNAseq) on omental metastasis from HGSOC patients. Analysis of 64,097 immune cells showed that ne...
Effective treatment of high grade serous ovarian cancer (HGSOC) still represents a clinical challenge. This is partially due to poor understanding of the complexity of this disease and the highly immunosuppressive tumor microenvironment (TME) that makes HGSOC resistant to most of the newly discovered therapies. The lack of relevant and physiologica...
Chimeric antigen receptor (CAR)-T cell therapies have a curative effect in some hematologic cancers, but limited efficacy in solid tumors. Using human 3-dimentional (3D) in vitro cell models of increasing complexity, we investigated barriers to CAR-T cell activity in high grade serous ovarian cancer (HGSOC), a disease with poor immunotherapy respon...
Heart failure remains one of the largest clinical burdens globally, with little to no improvement in the development of disease-eradicating therapeutics. Integrin targeting has been used in the treatment of ocular disease and cancer, but little is known about its utility in the treatment of heart failure. Here we sought to determine whether the sec...
Non-coding mutations (NCMs) that perturb the function of cis-regulatory elements (CRE, enhancers) contribute to cancer. Due to the vast search space, mutation abundance and indirect activity of non-coding sequences, it is challenging to identify which somatic NCMs are contributing to tumour development and progression. Here, we focus our investigat...
Non-coding mutations (NCMs) that perturb the function of cis -regulatory elements (CRE, enhancers) contribute to cancer. Due to the vast search space, mutation abundance and indirect activity of non-coding sequences, it is challenging to identify which somatic NCMs are contributing to tumour development and progression. Here, we focus our investiga...
Recent studies have shown that the tumor extracellular matrix (ECM) associates with immunosuppression, and that targeting the ECM can improve immune infiltration and responsiveness to immunotherapy. A question that remains unresolved is whether the ECM directly educates the immune phenotypes seen in tumors. Here, we identify a tumor-associated macr...
We asked if single-cell RNA sequencing (scRNA-seq) analysis of tumor immune cells in high-grade serous ovarian cancer (HGSOC) would reveal ways to enhance effects of neo-adjuvant chemotherapy (NACT). Analysis of 64,097 immune cells from seven HGSOC omental metastases showed that positive effects of NACT on immune responses were counterbalanced by i...
Following a ‘deconstruction’ of the metastatic tumor microenvironment (TME) of high grade serous ovarian cancer (HGSOC), we developed 3-dimensional (3D) human multicellular in vitro models using patient-derived primary cells and HGSOC malignant cell lines. In this study, we used these 3D in vitro human models to study how malignant cells influence...
In this study we explored the effects of chemotherapy on the extracellular matrix of high-grade serous ovarian cancer metastasis (HGSOC) at structural-textural protein level and transcriptionally, in order to identify the microenvironmental features that accompany a successful response. We studied two murine orthotopic, transplantable syngeneic mod...
Chimeric antigen receptor (CAR)-T cell therapies have promising outcomes in hematologic malignancies but limited activity in solid tumors. We used 3-dimentional (3D) in vitro human cell models of increasing complexity to investigate resistance to CAR-T cell therapy in high grade serous ovarian cancer (HGSOC), a disease with poor response to immunot...
Patients with myelodysplastic syndrome and ring sideroblasts (MDS-RS) present with symptomatic anemia due to ineffective erythropoiesis that impedes their quality of life and increases morbidity. More than 80% of patients with MDS-RS harbor splicing factor 3B subunit 1 (SF3B1) mutations, the founder aberration driving MDS-RS disease. Here, we repor...
Background
A major driver of cancer chromosomal instability is replication stress, the slowing or stalling of DNA replication. How replication stress and genomic instability are connected is not known. Aphidicolin-induced replication stress induces breakages at common fragile sites, but the exact causes of fragility are debated, and acute genomic c...
Some patients with advanced clear cell ovarian cancer (CCOC) respond to immunotherapy; however, little is known about the tumor microenvironment (TME) of this relatively rare disease. Here, we describe a comprehensive quantitative and topographical analysis of biopsies from forty-five patients, nine with FIGO stage I/II (early CCOC) and thirty-six...
Recent studies have shown the tumor extracellular matrix (ECM) associates with immunosuppression, and that targeting the ECM can improve immune infiltration and immunotherapy response. A question that remains is whether the ECM is directly educating the immune phenotypes seen in cancer. We identified a tumor-associated macrophage (TAM) population c...
Objectives
Resistance to cancer therapy is an enduring challenge and accurate and reliable preclinical models are lacking. We interrogated this unmet need using high grade serous ovarian cancer (HGSC) as a disease model.
Methods
We created five in vitro and two in vivo platinum-resistant HGSC models and characterised the entire cell panel via whol...
Precise vascular patterning is critical for normal growth and development. The ERG transcription factor drives Delta like ligand 4 (DLL4)/Notch signalling and is thought to act as pivotal regulators of endothelial cell (EC) dynamics and developmental angiogenesis. However, molecular regulation of ERG activity remains obscure. Using a series of EC s...
We have assessed the utility of 3-dimensional (3D) in vitro human cell models to understand barriers to chimeric antigen receptor (CAR)-T cell activity in high-grade serous ovarian cancer, (HGSOC) a disease with a poor response to immunotherapy. We defined mucin-1 (MUC1) as a potential target in HGSOC biopsies and the HGSOC cell lines, OvCAR3 and G...
This paper investigates mechanisms of resistance to the VEGF receptor inhibitor cediranib in high-grade serous ovarian cancer, HGSOC, and defines rational combination therapies. We used three different syngeneic orthotopic mouse HGSOC models that replicated the human tumor microenvironment, TME. After 4-5 weeks treatment of established tumors, cedi...
Myelodysplastic syndrome (MDS) is a hematological clonal stem cell disease. Recurrent splicing factors mutations are reported in 50% of MDS. Interestingly, mutations in the splicing factor gene SF3B1 are over-represented in MDS with ring sideroblasts (MDS-RS), co-occurring in up to 90% of patients. In MDS-RS, anemia is the major clinical manifestat...
The tumor microenvironment evolves during malignant progression, with major changes in nonmalignant cells, cytokine networks, and the extracellular matrix (ECM). In this study, we aimed to understand how the ECM changes during neoplastic transformation of serous tubal intraepithelial carcinoma lesions (STIC) into high-grade serous ovarian cancers (...
Duchenne muscular dystrophy (DMD) is caused by dystrophin gene mutations leading to skeletal muscle weakness and wasting. Dystrophin is enriched at the neuromuscular junction (NMJ), but how NMJ abnormalities contribute to DMD pathogenesis remains unclear. Here, we combine transcriptome analysis and modeling of DMD patient-derived neuromuscular circ...
p>Studying the complexity of the tumor microenvironment (TME) still represents a challenge in research. The intricate communication within the stroma - fibroblast, immune cells, endothelial cells and the extracellular matrix (ECM) - and the malignant cell compartment sustains every stage of cancer progression and resistance to cancer therapies, but...
The aim of this study was to investigate the effects of cediranib and understand mechanisms of resistance in syngeneic mouse models of high grade serious ovarian cancer (HGSOC). Cediranib, a VEGFR targeting agent, improves progression free survival in ovarian cancer patients but the benefits can be short lived. We recently conducted an extensive an...
p>Treatment of advanced Clear Cell Ovarian Cancer (CCOC) with immune checkpoint inhibition (ICI) is currently undergoing evaluation in a Phase II clinical trial. ARID1A mutations, which occur in up to 57% of CCOC, influence immune cell infiltration in pre-clinical models, but more information is needed on how it alters the tumor microenvironment (T...
p>The aim of this study is to characterize and validate similarities between the human tumor microenvironment (TME) and the TME of new HGSOC murine models and to use the models to analyze the role of tumor associated macrophages (TAMs) after chemotherapy. HGSOC has seen in the past decades only a modest reduction of mortality. This is in part due t...
Determining the tissue- and disease-specific circuit of biological pathways remains a fundamental goal of molecular biology. Many components of these biological pathways still remain unknown, hindering the full and accurate characterization of biological processes of interest. Here we describe ACSNI, an algorithm that combines prior knowledge of bi...
Guided by a multi-level ‘deconstruction’ of omental metastases, we developed a tetra (four cell)-culture model of primary human mesothelial cells, fibroblasts, adipocytes and high-grade serous ovarian cancer, HGSOC, cell lines. This multi-cellular model replicated key elements of human metastases and allowed malignant cell invasion into the artific...
In a multi-level ‘deconstruction’ of omental metastases, we previously identified a prognostic matrisome gene expression signature in high-grade serous ovarian cancer (HGSOC) and twelve other malignancies. Here, our aim was to understand how six of these extracellular matrix, ECM, molecules, COL11A1, COMP, FN1, VCAN, CTSB and COL1A1, are up-regulat...
Neoadjuvant chemotherapy (NACT) may stimulate anti-cancer adaptive immune responses in high-grade serous ovarian cancer (HGSOC), but little is known about effects on innate immunity. Using omental biopsies from HGSOC, and omental tumors from orthotopic mouse HGSOC models that replicate the human tumor microenvironment, we studied the impact of plat...
[This corrects the article DOI: 10.1093/narcan/zcab009.].
In a multi-level "deconstruction" of omental metastases, we previously identified a prognostic matrisome gene expression signature in high-grade serous ovarian cancer (HGSOC) and twelve other malignancies. Here, our aim was to understand how six of these extracellular matrix, ECM, molecules, COL11A1, COMP, FN1, VCAN, CTSB and COL1A1, are up-regulat...
The basement membrane (BM) is a special type of extracellular matrix and presents the major barrier cancer cells have to overcome multiple times to form metastases. Here we show that BM stiffness is a major determinant of metastases formation in several tissues and identify netrin-4 (Net4) as a key regulator of BM stiffness. Mechanistically, our bi...
Glioblastoma (GBM) is the most common and aggressive intrinsic brain tumour in adults. Epigenetic mechanisms controlling normal brain development are often dysregulated in GBM. Among these, BMI1, a structural component of the Polycomb Repressive Complex 1 (PRC1), which promotes the H2AK119ub catalytic activity of Ring1B, is upregulated in GBM and i...
Chromosomal instability (CIN) comprises continual gain and loss of chromosomes or parts of chromosomes and occurs in the majority of cancers, often conferring poor prognosis. Because of a scarcity of functional studies and poor understanding of how genetic or gene expression landscapes connect to specific CIN mechanisms, causes of CIN in most cance...
Resistance to therapy is an enduring challenge in cancer care. Here we interrogate this critical unmet need using high grade serous ovarian cancer (HGSC) as a disease model. We have generated a unique panel of platinum-resistant HGSC models and shown that they share multiple transcriptomic features with relapsed human HGSC. Moreover, they evolve di...
p>Despite the onset of new treatment strategies, mortality rates for breast cancer are estimated at approximately 600,000 women per year, mostly due to acquired resistance to therapy. Chemotherapy, often combination therapy, includes DNA-damaging agents such as epirubicin, an epimer of doxorubicin. Although chemotherapy has been reported to reduce...
Although there are many prospective targets in the tumor microenvironment (TME) of high-grade serous ovarian cancer (HGSOC), pre-clinical testing is challenging, especially as there is limited information on the murine TME. Here, we characterize the TME of six orthotopic, transplantable syngeneic murine HGSOC lines established from genetic models a...
Background
We previously showed that a major driver of cancer chromosomal instability (CIN) is replication stress, the slowing or stalling of DNA replication. However, the precise drivers of replication stress in cancer and the mechanisms by which these cause CIN and influence tumour evolution remain unclear. Common fragile sites are well-known gen...
Coronary microvascular dysfunction combined with maladaptive cardiomyocyte morphology and energetics are major contributors to heart failure advancement. Thus, dually enhancing cardiac angiogenesis and targeting cardiomyocyte function to slow, or reverse, the development of heart failure is a logical step towards improved therapy. We present eviden...
Many tumours have abundant macrophage populations. Tumour-associated macrophages (TAMs) frequently have tumour promoting roles and are associated with poor clinical outcome. We hypothesise that targeting TAMs in high-grade serous ovarian cancer (HGSOC) may improve response to chemotherapy.
We have assessed the effects of chemotherapy on TAM populat...
Many tumours have abundant macrophage populations. Tumour-associated macrophages (TAMs) frequently have tumour promoting roles and are associated with poor clinical outcome. We hypothesise that targeting TAMs in high-grade serous ovarian cancer (HGSOC) may improve response to chemotherapy.
We have assessed the effects of chemotherapy on TAM populat...
B cells are salient features of pancreatic ductal adenocarcinoma (PDAC) tumors, yet their role in this disease remains controversial. Murine studies have indicated a protumoral role for B cells, whereas clinical data show tumor-infiltrating B cells are a positive prognostic factor, both in PDAC and other cancers. This disparity needs to be clarifie...
Immunoglobulin response in KPC mice. (A) Representative immunofluorescence images of immunoglobulin deposition of IgG1 (green) and IgG2a/b (white) near EpCAM positive pancreatic cells (red) where DAPI (blue) was used as a nuclear marker in healthy pancreas and isotype controls. The same settings were used for acquiring images from healthy and tumor...
No upregulation of immunosuppressive cytokine Il10 in KPC tumor-derived B cells. (A) Gene expression of Il10 in B cells isolated from healthy spleen (Pdx-1Cre), and the spleen and tumor of KPC mice. Gene expression was measured on the RT2 Profiler™ PCR Array Mouse Cancer Inflammation & Immunity Crosstalk. The expression is normalized to the house k...
The effect of B cell depletion in orthotopic PDAC. (A) Representative immunofluorescence images of absent immunoglobulin deposition of IgG1 (green channel) and IgG2a/b (white channel) near EpCAM positive tumor cells (red) where DAPI (blue) was used as a nuclear marker in μMT−/− tumors (n = 6). (B) Flow cytometry analysis of tumors of WT and μMT−/−...
Analysis of B cells in murine PDAC. (A) Representative flow cytometry gating strategy to exclude debris, doublets, and non-viable cells (FVD, fixable viability dye). B cells were gated as CD45+ CD19+. (B) KPC tumor sections were stained with B220 (red) as a marker of B cells and E-Cadherin (white) as an epithelial and tumor cell marker. DAPI was us...
Characterization of the effects of anti-CD20 B-cell depletion in KPC mice. (A) Flow cytometry analysis of the percentage of CD19+ cells out of CD45+ cells in the spleen, mesenteric lymph node and blood of KPC mice treated with PBS (n = 5), IgG2a (n = 5) or anti-CD20 (n = 5–7). (B) Flow cytometry of CD138hi plasma cells out of total live cells in th...
Antibodies used for flow cytometry.
Antibodies used in immunofluorescence and immunohistochemistry.
Isotype antibody controls used in immunofluorescence and immunohistochemistry.
Secondary antibodies used in immunohistochemistry.
Until recently, it was thought that high-grade serous ovarian cancer (HGSOC) arises from the ovarian surface epithelium (OSE). Now, it has become clear that the epithelium of the fallopian tube fimbriae is the starting point of many HGSOCs. Serous tubal intraepithelial carcinomas (STICs) are suggested to be the earliest form of HGSOC and show mutat...
Standard of care for multiple myeloma involves autologous hematopoietic cell transplant (AHCT), which can extend life by a year; however the disease remains incurable. A dendritic cell vaccine developed at Moffitt will be used both immediately before and after AHCT, with the aim of achieving complete response. Data will be collected during the tria...
We have profiled, for the first time, an evolving human metastatic microenvironment by measuring gene expression, matrisome proteomics, cytokine and chemokine levels, cellularity, extracellular matrix organization, and biomechanical properties, all on the same sample. Using biopsies of high-grade serous ovarian cancer metastases that ranged from mi...
We have profiled, for the first time, an evolving human metastatic microenvironment by measuring gene expression, matrisome proteomics, cytokine and chemokine levels, cellularity, extracellular matrix organization, and biomechanical properties, all on the same sample. Using biopsies of high-grade serous ovarian cancer metastases that ranged from mi...
The purpose of this study was to understand the relationships between the molecular mechanisms of disease progression and higher-order features such as tissue stiffness, extent of disease and cellularity in the tumor microenvironment, TME. Using samples of human high-grade serous ovarian cancer metastases, ranging from normal to heavily diseased, w...
Elevated expression of the chemokine receptor CCR4 in tumors is associated with poor prognosis in several cancers. Here, we have determined that CCR4 was highly expressed in human renal cell carcinoma (RCC) biopsies and observed abnormal levels of CCR4 ligands in RCC patient plasma. An antagonistic anti-CCR4 antibody had antitumor activity in the R...
Purpose:
In high-grade serous ovarian cancer (HGSOC), higher densities of both B cells and the CD8+ T cell infiltrate were associated with a better prognosis. However, the precise role of B cells in the anti-tumor response remains unknown. As peritoneal metastases are often responsible for relapse, our aim was to characterize the role of B cells i...
Genes encoding the histone H3 lysine 4 methyltransferases KMT2C and KMT2D are subject to deletion and mutation in pancreatic ductal adenocarcinoma (PDAC), where these lesions identify a group of patients with a more favorable prognosis. In this study, we demonstrate that low KMT2C and KMT2D expression in biopsies also defines better outcome groups,...
Focal adhesion kinase (FAK) promotes anti-tumor
immune evasion. Specifically, the kinase activity of
nuclear-targeted FAK in squamous cell carcinoma
(SCC) cells drives exhaustion of CD8+ T cells and
recruitment of regulatory T cells (Tregs) in the tumor
microenvironment by regulating chemokine/cytokine
and ligand-receptor networks, including via tr...
Purpose:Vaccinia virus (VV) has strong potential as a novel therapeutic agent for treatment of pancreatic cancer (PaCa). We investigated whether arming VV with IL10 could enhance the antitumor efficacy with the view that IL10 might dampen the host immunity to the virus, increasing viral persistence thus maximising the oncolytic effect and antitumor...
Metastasis is the main cause of cancer-related death and thus understanding the molecular and cellular mechanisms underlying this process is critical. Here, our data demonstrate, contrary to established dogma, that loss of haematopoietic-derived focal adhesion kinase (FAK) is sufficient to enhance tumour metastasis. Using both experimental and spon...
Tumor microenvironments posses complex chemokine networks that contribute to the extent and phenotype of the host infiltrate. Malignant cells may gain functional chemokine receptors, often as a consequence of oncogenic mutations, allowing them to respond to distant chemokine gradients during metastasis. The chemokine receptor CCR4 was highly expres...
Background
The myeloid/lymphoid or mixed-lineage leukaemia 2 (MLL2) histone methyltransferase (referred to as Mll4 in mice) forms part of a large multiprotein complex, which catalyses the methylation of lysine 4 on histone H3 (H3K4). High levels of this histone modification are detected at promoter regions of actively transcribed genes. Loss-of-fun...
Interleukin-17 (IL-17) released in the tumor microenvironment in response to drugs blocking vascular endothelial growth factor (VEGF) triggers stromal-derived inflammatory and VEGF-independent angiogenic programs that induce the drug refractoriness found in cancers resistant to anti-angiogenic therapy.
Alternatively activated macrophages express the pattern recognition receptor scavenger receptor A (SR-A). We demonstrated previously that coculture of macrophages with tumor cells upregulates macrophage SR-A expression. We show in this study that macrophage SR-A deficiency inhibits tumor cell migration in a coculture assay. We further demonstrate t...
Nuclear factor-βB; (NF-κB) controls a range of genes involved in inflammation, cell survival, growth and apoptosis. The dysregulated NF-κB pathway has been found to be involved in carcinogenesis and cancer progression. An IKKα-deleted mouse pancreatic cancer cell line was generated using a lentiviral construct with an shRNA. We investigated the eff...
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Introduction
In vitro stimulation of macrophages can produce classically activated (M1) or alternatively activated (M2) phenotypes. In various solid tumors, tumor associated macrophages (TAM) have been described as approximating an M2 phenotype and are potentially pro-tumoral. We are testing the hypothesis that TAM play an important role in t...
The majority of human pancreatic cancers have activating mutations in the KRAS proto-oncogene. These mutations result in increased activity of the NF-κB pathway and the subsequent constitutive production of proinflammatory cytokines. Here, we show that inhibitor of κB kinase 2 (Ikk2), a component of the canonical NF-κB signaling pathway, synergizes...
The role of interleukin (IL)-17 and the IL-17-producing T helper (Th)17 cells in cancer has recently become the focus of extensive investigation. An expanding body of literature implicates Th17 cells and their hallmark cytokine in both pro- and anti-tumourigenic processes. In this review we describe their biological activities and outline the recip...
Systemic lupus erythematosus is a multisystem autoimmune disease characterized by the production of numerous antinuclear autoantibodies and inflammatory mediators. The BXSB mouse strain is an excellent model of the disease. Previous work has determined a number of important disease susceptibility intervals that have been isolated in separate congen...