Simone P Niclou

Simone P Niclou
LIH Luxembourg Institute of Health | CRP Santé · Department of Oncology

PhD

About

282
Publications
37,565
Reads
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9,883
Citations
Citations since 2017
132 Research Items
6471 Citations
201720182019202020212022202302004006008001,0001,2001,400
201720182019202020212022202302004006008001,0001,2001,400
201720182019202020212022202302004006008001,0001,2001,400
201720182019202020212022202302004006008001,0001,2001,400
Additional affiliations
April 2005 - present
LIH Luxembourg Institute of Health
Position
  • Principal Investigator

Publications

Publications (282)
Article
The mainstay of treatment for adult patients with gliomas, glioneuronal and neuronal tumors consists of combinations of surgery, radiotherapy and chemotherapy. For many systemic cancers, targeted treatments are a part of standard of care, however the predictive significance of most of these targets in CNS tumors remains less well studied. Despite t...
Article
Glioma cellular heterogeneity and plasticity represent fundamental obstacles to effective therapies. Understanding the determinants that govern glioma cell diversity and adaptability is critical to overcoming treatment resistance. Recent single cell DNA methylation studies have demonstrated that dynamic epigenetic alterations facilitate glioma cell...
Article
Background: Numerous patient-based studies have highlighted the protective role of immunoglobulin E-mediated allergic diseases on glioblastoma (GBM) susceptibility and prognosis. However, the mechanisms behind this observation remain elusive. Our objective was to establish a preclinical model able to recapitulate this phenomenon and investigate th...
Article
Full-text available
Brain disorders represent 32% of the global disease burden, with 169 million Europeans affected. Constraint-based metabolic modelling and other approaches have been applied to predict new treatments for these and other diseases. Many recent studies focused on enhancing, among others, drug predictions by generating generic metabolic models of brain...
Article
Full-text available
In glioblastoma (GBM), tumour‐associated microglia/macrophages (TAMs) represent the major cell type of the stromal compartment and contribute to tumour immune escape mechanisms. Thus, targeting TAMs is emerging as a promising strategy for immunotherapy. However, TAM heterogeneity and metabolic adaptation along GBM progression represent critical fea...
Article
Glioblastomas are incurable tumors infiltrating the brain. A subpopulation of glioblastoma cells forms a functional and therapy-resistant tumor cell network interconnected by tumor microtubes (TMs). Other subpopulations appear unconnected, and their biological role remains unclear. Here, we demonstrate that whole-brain colonization is fueled by gli...
Article
The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct...
Article
Full-text available
Glioblastoma (GBM) is the most aggressive primary brain tumor characterized by infiltrative growth of malignant glioma cells into the surrounding brain parenchyma. In this study, our analysis of GBM patient cohorts revealed a significant higher expression of Glycosyltransferase 8 domain containing 1 (GLT8D1) compared to normal brain tissue and coul...
Article
Full-text available
Phenotypic plasticity has emerged as a major contributor to intra-tumoral heterogeneity and treatment resistance in cancer. Increasing evidence shows that glioblastoma (GBM) cells display prominent intrinsic plasticity and reversibly adapt to dynamic microenvironmental conditions. Limited genetic evolution at recurrence further suggests that resist...
Article
Multiomic single nucleus RNA- and ATACseq profiling reveals regulators of glioma cell state diversity. The extensive intra- and intertumoral heterogeneity observed in glioma reflects the resistance to therapy and poor prognosis observed clinically. Single-cell sequencing studies have highlighted that glioma heterogeneity reflects the co-existence o...
Article
BACKGROUND Numerous epidemiological studies have highlighted the protective role of immunoglobulin E-mediated allergic diseases on glioblastoma (GBM) susceptibility and prognosis. However, the mechanistic explanations behind these phenomena remain unexplored. Our objective was to set up a preclinical model and investigate the mechanisms underlying...
Article
BACKGROUND Glioblastomas are among the most heterogeneous tumors, which hampers patient stratification and development of effective therapies. Glioblastomas create a dynamic ecosystem, where heterogeneous tumor cells interact with the tumor microenvironment to establish different niches. Upon tumor growth, Glioblastoma cells manifest remarkable pla...
Article
Full-text available
Replication-associated single-ended DNA double-strand breaks (seDSBs) are repaired predominantly through RAD51-mediated homologous recombination (HR). Removal of the non-homologous end-joining (NHEJ) factor Ku from resected seDSB ends is crucial for HR. The coordinated actions of MRE11-CtIP nuclease activities orchestrated by ATM define one pathway...
Preprint
Full-text available
Tumor adaptation or selection is thought to underlie therapy resistance of gliomas. To investigate the longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 143 matched initial and recurrent patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) gliomas. IDHwt gliomas showed a l...
Article
Full-text available
H-1 parvovirus (H-1PV) is a promising anticancer therapy. However, in-depth understanding of its life cycle, including the host cell factors needed for infectivity and oncolysis, is lacking. This understanding may guide the rational design of combination strategies, aid development of more effective viruses, and help identify biomarkers of suscepti...
Article
Full-text available
Tumor organoids and patient-derived orthotopic xenografts (PDOXs) are some of the most valuable pre-clinical tools in cancer research. In this protocol, we describe efficient derivation of organoids and PDOX models from glioma patient tumors. We provide detailed steps for organoid culture, intracranial implantation, and detection of tumors in the b...
Article
Full-text available
Background Mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) define glioma subtypes and are considered primary events in gliomagenesis, impacting tumor epigenetics and metabolism. IDH enzyme activity is crucial for the generation of reducing potential in normal cells, yet the impact of the mutation on the cellular antioxidant system in glioma i...
Article
Full-text available
Serine catabolism via the folate cycle provides formate that is essential for nucleotide synthesis in proliferating cells. In addition to this canonical function to support biomass production in anabolic cells, we have recently demonstrated in vitro and in vivo that formate production in cancer cells is often in excess of the anabolic demand. This...
Article
Full-text available
Mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) define glioma subtypes and are considered primary events in gliomagenesis, impacting tumor epigenetics and metabolism. IDH enzymes are crucial for the generation of reducing potential, yet the impact of the mutation on the cellular antioxidant system is not understood. Here, we investigate how g...
Article
Full-text available
The infiltrative nature of Glioblastoma (GBM), the most aggressive primary brain tumor, critically prevents complete surgical resection and masks tumor cells behind the blood brain barrier reducing the efficacy of systemic treatment. Here, we use a genome-wide interference screen to determine invasion-essential genes and identify the AN1/A20 zinc f...
Article
Full-text available
Malignant brain tumors remain uniformly fatal, even with the best-to-date treatment. For Glioblastoma (GBM), the most severe form of brain cancer in adults, the median overall survival is roughly over a year. New therapeutic options are urgently needed, yet recent clinical trials in the field have been largely disappointing. This is partially due t...
Article
Full-text available
Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the establishment a large cohort of unique organoids and patient-derived orthotopic xenografts (PDOX) of various glioma subtypes, including gliomas with mutations in IDH1, and paired longitudinal...
Article
Intratumoral heterogeneity is one of the major barriers in the treatment of many tumor types. In glioblastoma (GBM) – the most aggressive brain tumor - survival of patients following standard therapy has stagnated to an average of 14 months, largely due to the inherent heterogeneity and phenotypic plasticity. Patient-derived orthotopic xenografts (...
Article
Patient-derived cancer models are essential tools for studying tumor biology and for preclinical interventions. Although numerous clinical cancer trials are being conducted, many fail due to inappropriate selection of compounds at the preclinical stage. Therefore, better preclinical models are crucial for predicting successful clinical impact. Orth...
Chapter
Malignant gliomas including Glioblastoma (GBM) are characterized by extensive diffuse tumor cell infiltration throughout the brain, which represents a major challenge in clinical disease management. While surgical resection is beneficial for patient outcome, it is well recognized that tumor cells at the invasive front or beyond stay behind and cons...
Article
Full-text available
Resistance to chemotherapy by temozolomide (TMZ) is a major cause of glioblastoma (GBM) recurrence. So far, attempts to characterize factors that contribute to TMZ sensitivity have largely focused on protein-coding genes, and failed to provide effective therapeutic targets. Long noncoding RNAs (lncRNAs) are essential regulators of epigenetic-driven...
Article
Full-text available
Glioblastoma (GBM) represents the most common primary malignancy of the central nervous system in adults, and remains a largely incurable disease. The elucidation of disease subtypes based on mutational profiling, gene expression and DNA methylation has so far failed to translate into improved clinical outcomes. However, new knowledge emerging from...
Conference Paper
Background: Standard-of-care for glioblastoma (GBM) includes surgery, radiation and temozolomide (TMZ). Nearly all tumors recur and 5-year survival is less than 3%. Unmethylated promoter status for O⁶-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for TMZ-resistance. Second-line treatment with bevacizumab has failed to improve...
Preprint
Full-text available
Patient-derived cancer models are essential tools for studying tumor biology and preclinical interventions. Here, we show that glioma patient-derived orthotopic xenografts (PDOXs) enable long-term propagation of patient tumors and represent clinically relevant patient avatars. We created a large collection of PDOXs from primary and recurrent glioma...
Preprint
Full-text available
Unrepaired O6-methylguanine lesions induced by the alkylating chemotherapy agent temozolomide lead to replication-associated single-ended DNA double-strand breaks (seDSBs) that are repaired predominantly through RAD51-mediated homologous recombination (HR). Here, we show that loss of the pre-mRNA splicing and DNA repair protein XAB2 leads to increa...
Article
Full-text available
Myocardial infarction (MI) is a leading cause of death worldwide. Reperfusion is considered as an optimal therapy following cardiac ischemia. However, the promotion of a rapid elevation of O2 levels in ischemic cells produces high amounts of reactive oxygen species (ROS) leading to myocardial tissue injury. This phenomenon is called ischemia reperf...
Article
Full-text available
Cancer heterogeneity and progression are subject to complex interactions between neoplastic cells and their microenvironment, including the immune system. Although glioblastomas (GBMs) are classified as ‘cold tumours’ with very little lymphocyte infiltration, they can contain up to 30–40% of tumour-associated macrophages, reported to contribute to...
Article
Background Women represent an increasing proportion of the overall workforce in medicine but are underrepresented in leadership roles. Methods To explore gender inequalities and challenges in career opportunities, a web-based survey was conducted among the membership of the European Association of Neuro-Oncology and the Brain Tumor Group of the Eu...
Article
Full-text available
IDH1R132H (isocitrate dehydrogenase 1) mutations play a key role in the development of low-grade gliomas. IDH1wt converts isocitrate to α-ketoglutarate while reducing nicotinamide adenine dinucleotide phosphate (NADP+), whereas IDH1R132H uses α-ketoglutarate and NADPH to generate the oncometabolite 2-hydroxyglutarate (2-HG). While the effects of 2-...
Article
Full-text available
The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we f...
Article
BACKGROUND A major hallmark of glioblastoma (GBM) is its invasive capacity, contributing to its aggressive behaviour. Invasive cells cannot be easily removed by surgery or irradiation and eventually result in lethal recurrence. A better understanding of the invasion process and the key molecular players underlying the invasive potential of GBM may...
Article
BACKGROUND Cellular heterogeneity is a hallmark of numerous cancer types, including Glioblastoma (GBM). Cancer stem cells (CSC) have been accounted for the generation of phenotypic heterogeneity and tumor progression in GBM. Recent data, however, suggest that CSCs may not represent a stable entity and intrinsic plasticity plays a key role in tumor...
Article
INTRODUCTION Aberrant regulation of receptor tyrosine kinase (RTK) activity is characteristic of Glioblastoma (GBM). However, RTK-based targeted therapies have been largely unsuccessful in GBM patients, partially due to the complexity and redundance of RTK signaling. LRIG1 (Leucine-rich Repeats and ImmunoGlobulin-like domains 1) is an important end...
Article
BACKGROUND High grade glioma (HGG) patients develop resistance to standard treatment leading to disease progression and limited life expectancy. Recent advances in the molecular characterisation of treatment-naïve HGGs based on next generation sequencing and DNA methylation analyses have led to a better delineation of HGG-subtypes and identificatio...
Article
Treatment options for adult patients with glioma has remained largely unchanged over the past three decades. Targeted inhibitors and immunotherapies have improved outcomes for many cancer types but their relevance in glioma is unclear. The inevitability of glioma disease recurrence demands an understanding of mechanisms driving therapy resistance....
Article
Full-text available
Background Targeted approaches for inhibiting epidermal growth factor receptor (EGFR) and other receptor tyrosine kinases (RTKs) in glioblastoma (GBM) have led to therapeutic resistance and little clinical benefit, raising the need for the development of alternative strategies. Endogenous LRIG1 (Leucine-rich Repeats and ImmunoGlobulin-like domains...
Article
BACKGROUND Cellular heterogeneity has been well established within numerous cancer types, including malignant brain tumours. Initially, cancer stem cells (CSC) have been accounted for formation of phenotypic heterogeneity and tumor progression in glioblastoma (GBM). Recent data, however, suggest that CSCs may not represent a stable entity and intri...
Article
INTRODUCTION Aberrant regulation of receptor tyrosine kinase (RTK) activity is characteristic of Glioblastoma (GBM). However, RTK-based targeted therapies have been largely unsuccessful in GBM patients, partially due to the complexity and redundance of RTK signaling. LRIG1 (Leucine-rich Repeats and ImmunoGlobulindomains protein 1) is known as an en...
Article
BACKGROUND A major hallmark of glioblastoma (GBM) is its highly invasive capacity, contributing to its aggressive behaviour. Since invasive cells cannot be easily removed by surgery or irradiation, they are left behind and eventually result in lethal recurrence. Therefore, a better understanding of the invasion process and of the key molecular play...
Article
BACKGROUND High grade glioma (HGG) patients develop resistance to standard treatment leading to disease progression and limited life expectancy. Advances in the molecular characterisation of treatment-naïve HGGs based on next-generation sequencing and DNA methylation analyses have led to a better delineation of HGG subtypes and the identification o...
Conference Paper
Background: Standard-of-care for glioblastoma (GBM) includes surgery, radiation and temozolomide (TMZ). Nearly all tumors recur and 5-year survival is less than 3%. Unmethylated promoter status for O⁶-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for TMZ-resistance. Second-line treatment with bevacizumab has not only failed to...
Conference Paper
Background: Standard-of-care for glioblastoma (GBM) includes surgery, radiation and temozolomide (TMZ). Nearly all tumors recur and 5-year survival is less than 3%. Unmethylated promoter status for O⁶-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for TMZ-resistance. Second-line treatment with bevacizumab has not only failed to...
Article
Full-text available
First thought to orchestrate exclusively leukocyte trafficking, chemokines are now acknowledged for their multiple roles in the regulation of cell proliferation, differentiation, and survival. Dysregulation of their normal functions contributes to various pathologies, including inflammatory diseases and cancer. The two chemokine receptor 3 variants...
Article
Full-text available
The identity and unique capacity of cancer stem cells (CSC) to drive tumor growth and resistance have been challenged in brain tumors. Here we report that cells expressing CSC-associated cell membrane markers in Glioblastoma (GBM) do not represent a clonal entity defined by distinct functional properties and transcriptomic profiles, but rather a pl...
Article
Full-text available
Background : The topological analysis of networks extracted from different types of “omics” data is a useful strategy for characterizing biologically meaningful properties of the complex systems underlying these networks. In particular, the biological significance of highly connected genes in diverse molecular networks has been previously determine...
Article
Inevitable tumor recurrence and a poor median survival are frustrating reminders of the inefficacy of our current standard of care for patients with newly diagnosed glioblastoma (GBM), which includes surgery followed by radiotherapy and chemotherapy with the DNA alkylating agent temozolomide. Because resistance to genotoxic damage is achieved mainl...
Article
Full-text available
Background : The topological analysis of networks extracted from different types of “omics” data is a useful strategy for characterizing biologically meaningful properties of the complex systems underlying these networks. In particular, the biological significance of highly connected genes in diverse molecular networks has been previously determine...
Article
Full-text available
While the central nervous system is considered an immunoprivileged site and brain tumors display immunosuppressive features, both innate and adaptive immune responses affect glioblastoma (GBM) growth and treatment resistance. However, the impact of the major immune cell population in gliomas, represented by glioma‐associated microglia/macrophages (...
Article
Full-text available
Astrocytes play a significant role in coordinating neural development and provide critical support for the function of the CNS. They possess important adaptation capacities that range from their transition towards reactive astrocytes to their ability to undergo reprogramming, thereby revealing their potential to retain latent features of neural pro...
Presentation
A comprehensive characterization of the somatic alterations and molecular subtypes of glioma at diagnosis has been established. However, gliomas undergo significant molecular changes over time, some of these causing malignant progression or associated with therapy. Understanding this molecular evolution may uncover therapeutic vulnerabilities and f...
Article
Full-text available
It is well recognized that long term cell cultures are poor models to study human cancer, largely because of loss of clonal heterogeneity, accumulation or loss of genomic alterations and adaptation to a highly artificial environment. Patient-derived orthotopic xenografts (PDOX) based on organotypic three-dimensional tumor spheroids from human gliom...
Article
Standard-of-care for glioblastoma (GBM) includes surgery, radiation and temozolomide. Nearly all tumors recur and 5-year survival is less than 3%. Unmethylated promoter status for O⁶-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for temozolomide-resistance. Second-line treatment with bevacizumab has not only failed to improve...
Article
It is well recognized that long term cell cultures are poor models to study human cancer, largely because of loss of clonal heterogeneity, accumulation or loss of genomic alterations and adaptation to a highly artificial environment. Patient-derived orthotopic xenografts (PDOX) based on organotypic three-dimensional tumor spheroids from human gliom...