Monique Dontenwill

• team leader
• University of Strasbourg

BACKGROUND Brain cancers are the most frequently diagnosed tumor types in pediatric and young adult populations. Unfortunately, they often carry a poor prognosis and face common challenges such as treatment resistances due to intra- and intertumoral heterogeneity. To fully understand the intrinsic and extrinsic mechanisms which might hinder proper...

BACKGROUND Gliomatosis cerebri (GC), a rare form of high-grade glioma, is characterized by a particularly invasive phenotype within multiple lobes of the brain and a dismal prognosis. This entity was removed in 2016 of the WHO brain tumor classification because of an absence of specific GC driving molecular signature. Its diffusive aspect on MRI is...

BACKGROUND Aggressive brain cancers represent the most lethal forms of tumors in pediatric population. Their molecular drivers and co-alterations are currently guiding therapeutic strategies. Due to heterogeneous nature of these tumors, they are quickly developing resistance to treatment. Recognizing intrinsic and extrinsic mechanisms underlying th...

Brain cancers are the most incident and deadliest tumor types in pediatric and young adult populations. Among them, several histotypes are characterized by their molecular drivers and co-alterations currently guiding our therapeutic strategies. Due to inter- and intra-tumoral heterogeneity, those tumors are becoming rapidly chemo- and radioresistan...

Head and neck squamous cell carcinomas (HNSCCs) are heterogeneous tumors, well known for their frequent relapsing nature. To counter recurrence, biomarkers for early diagnosis, prognosis, or treatment response prediction are urgently needed. miRNAs can profoundly impact normal physiology and enhance oncogenesis. Among all of the miRNAs, the miR-30...

HIF-1a and HIF-2a are master regulators operating during tumor hypoxia. Few data are available on their role in pediatric high-grade gliomas (pHGGs), in which recent insights on metabolism and immunotolerance induction through hypoxia-driven mechanisms might opening the path to study further this process and their molecular actors. Our study invest...

Diffuse midline (DMG) and brainstem (DIPG) high-grade gliomas (HGG) bearing H3.3K27M driver mutation are aggressive and uncurable brain tumors. We evidenced by the past HIF-2a and its transcriptional gene, EPAS1, as a marker of resistance when targeting mTor/HIF-1a pathway. To understand HIF-2α potential role in chronically active hypoxic environme...

Tumor metabolism is emerging as a potential target for cancer therapies. This new approach holds particular promise for the treatment of glioblastoma, a highly lethal brain tumor that is resistant to conventional treatments, for which improving therapeutic strategies is a major challenge. The presence of glioma stem cells is a critical factor in th...

A growing body of experimental and clinical evidence suggests that rare cell populations, known as cancer stem cells (CSCs), play an important role in the development and therapeutic resistance of several cancers, including glioblastoma. Elimination of these cells is therefore of paramount importance. Interestingly, recent results have shown that t...

(1) Background: Epiregulin (EREG) is a ligand of EGFR and ErB4 involved in the development and the progression of various cancers including head and neck squamous cell carcinoma (HNSCC). Its overexpression in HNSCC is correlated with short overall survival and progression-free survival but predictive of tumors responding to anti-EGFR therapies. Bes...

Cationic polymers such as polyethylenimine (PEI) have found a pervasive place in laboratories across the world as gene delivery agents. However, their applications are not limited to this role, having found a place as delivery agents for drugs, in complexes known as polymer-drug conjugates (PDCs). Yet a potentially underexplored domain of research...

Glioblastoma (GBM) is the most deadly type of malignant brain tumor, despite extensive molecular analyses of GBM cells. In recent years, the tumor microenvironment (TME) has been recognized as an important player and therapeutic target in GBM. However, there is a need for a full and integrated understanding of the different cellular and molecular c...

The difficulty involved in the treatment of many tumours due to their recurrence and resistance to chemotherapy is tightly linked to the presence of cancer stem cells (CSCs). This CSC sub-population is distinct from the majority of cancer cells of the tumour bulk. Indeed, CSCs have increased mitochondrial mass that has been linked to increased sens...

Nucleic-acid aptamers are of strong interest for diagnosis and therapy. Compared with antibodies, they are smaller, stable upon variations in temperature, easy to modify, and have higher tissue-penetration abilities. However, they have been little described as detection probes in histology studies of human tissue sections. In this study, we perform...

Osteosarcoma (OS) is the most common primary bone cancer, where the overall 5‐year surviving rate is below 20% in resistant forms. Accelerating cures for those poor outcome patients remains a challenge. Nevertheless, several studies of agents targeting abnormal cancerous pathways have yielded disappointing results when translated into clinic becaus...

Cancer stem cells (CSCs) represent a difficult to treat cellular niche within tumours due to their unique characteristics, which give them a high propensity for resistance to classical anti-cancer treatments and the ability to re-populate the tumour mass. An attribute that may be implicated in the high rates of recurrence of certain tumours. Howeve...

Pediatric midline high-grade gliomas (pmHGG) are aggressive and incurable tumors of the central nervous system. There is a pressing need for novel therapeutic approaches to treat them. Therefore, proactive translational studies wish to go further discovering new targetable proteins and pathways. Our objectives are then to focus on the modulation of...

BRAF p.v600e mutation is encountered in brain tumors, mostly low grade pediatric diffuse gliomas (LGG) and epileptogenic glioneuronal tumors such as gangliogliomas (GG) or pleomorphic xanthoastrocytomas (PXA). Less frequently this mutation is present in high grade glial or glioneuronal tumors such as pleomorphic xanthoastrocytomas with anaplasia, a...

Background: Osteosarcomas (OTS) represent the most common primary bone cancer diagnosed in adolescents and young adults. Despite remarkable advances, there are no objective molecular or imaging markers able to predict an OTS outcome at diagnosis. Focusing on biomarkers contributing broadly to treatment resistance, we examine the interplay between...

Despite extensive treatment, glioblastoma inevitably recurs, leading to an overall survival of around 16 months. Understanding why and how tumours resist to radio/chemotherapies is crucial to overcome this unmet oncological challenge. Primary and acquired resistance to Temozolomide (TMZ), the standard-of-care chemotherapeutic drug, have been the su...

BACKGROUND Glioblastoma (GBM) is the most frequent and deadliest type of central nervous system tumors. Despite the treatment by the Stupp protocol, almost all patients relapse and new therapeutic protocols have been unsuccessful for ameliorating patient survival. Molecular heterogeneity of GBM and existence of glioma stem cells (GSC) may be linked...

Over the last decades, several techniques have been developed to study cell adhesion, however they present significant shortcomings. Such techniques mostly focus on strong adhesion related to specific protein-protein associations, such as ligand/receptor binding in focal adhesions. Therefore, weak adhesion, related to less specific or non-specific...

Integrin α5β1 was suggested to be involved in glioblastoma (GBM) aggressiveness and treatment resistance through preclinical studies and genomic analysis in patients. However, further protein expression data are still required to confirm this hypothesis. In the present study, we investigated by immunofluorescence the expression of integrin α5 and i...

The EGFR-targeting antibody cetuximab (CTX) combined with radiotherapy is the only targeted therapy that has been proven effective for the treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Recurrence arises in 50% of patients with HNSCC in the years following treatment. In clinicopathological practice, it is difficult...

Pediatric high-grade gliomas (pHGGs), including diffuse intrinsic pontine gliomas (DIPGs), despite their low incidence, are the leading cause of mortality in pediatric neuro-oncology. Frequently, pHGGs, harboring mainly histone mutations, are or become resistant to standard therapies like irradiation or chemotherapies. Recent insights showed in adu...

Background: Pediatric high-grade gliomas (pHGGs) are the leading cause of mortality in pediatric neuro-oncology, displaying frequent resistance to standard therapies. Profiling DNA repair and cell cycle gene expression has recently been proposed as a strategy to classify adult glioblastomas. To improve our understanding of the DNA damage response...

Simple Summary This review describes in a very detailed and exhaustive approach the literature of these last 20 years on glioblastoma targeted therapies in Phases II-IV of 257 clinical trials on adults with newly diagnosed or recurrent GBMs (excluding targeted immunotherapies and therapies targeting tumor cell metabolism, well documented in recent...

Overexpression of EGFR drives glioblastomas (GBM) cell invasion but these tumours remain resistant to EGFR-targeted therapies such as tyrosine kinase inhibitors (TKIs). Endocytosis, an important modulator of EGFR function, is often dysregulated in glioma cells and is associated with therapy resistance. However, the impact of TKIs on EGFR endocytosi...

Pediatric high-grade gliomas (pHGGs) have a very dismal prognosis and need new innovative strategy for treatment. Despite the past discovery of histone H3 driver mutations, we are not able for instance to stop this induced epigenetic remodulation. Therefore, proactive translational studies wish to go further discovering new targetable proteins in p...

BRAFv600e mutation is encountered mostly in low-grade pediatric gliomas (LGG) and epileptogenic glioneuronal tumors, such as gangliogliomas (GG). Less frequently this mutation is present in high-grade glial (HGG) or glioneuronal tumors. Recent publications were highlighting BRAF mutation and CDKN2A deletion, as independent prognostic factors linked...

Integrins are heterodimeric transmembrane proteins able to connect cells with the micro‐environment. They represent a family of receptors involved in almost all the hallmarks of cancer. Integrins recognizing the Arg‐Gly‐Asp (RGD) peptide in their natural extracellular matrix ligands have been particularly investigated as tumoral therapeutic targets...

Osteosarcoma is the most frequent primary bone tumor diagnosed during adolescence and young adulthood. It is associated with the worst outcomes in the case of poor response to chemotherapy and in metastatic disease. While no molecular biomarkers are clearly and currently associated with those worse situations, the study of pathways involved in the...

Osteosarcoma is the most common primary malignant bone tumor in children and young adults. Its immune environment was described as predominantly involving M2 macrophages or osteoclasts. Previous studies were observing ganglioside GD2 expression on the osteosarcoma cell surface. Even more and more publications are deciphering the role of hypoxic bio...

Glioblastoma (GBM) is one of the most aggressive types of cancer, which begins within the brain. It is the most invasive type of glioma developed from astrocytes. Until today, Temozolomide (TMZ) is the only standard chemotherapy for patients with GBM. Even though chemotherapy extends the survival of patients, there are many undesirable side effects...

Pediatric high-grade gliomas (pHGGs) represent a very dismal disease that is needing new innovative compound for treatment. Despite the past discovery of histone H3 driver mutations, we are not able for instance to stop this induced process on epigenetic remodulation. Therefore, there is since a decade proactive works aimed to discover new targetab...

Osteosarcoma is the first bone cancer diagnosed in adolescent and young adults. Multiple studies involved a deregulation of osteoblast, osteoclast, or microenvironment genes in their development and progression. Nevertheless, no focus was already done in the oxygen-modulated environment of those cancers. Our objectives in this study were to determi...

The brain tumor microenvironment has recently become a major challenge in all pediatric cancers, but especially in brain tumors like high-grade gliomas. Hypoxia is one of the extrinsic tumor features that interacts with tumor cells, but also with the blood–brain barrier and all normal brain cells. It is the result of a dramatic proliferation and ex...

Background: Pediatric high-grade gliomas (pHGGs) are facing a very dismal prognosis and representative pre-clinical models are needed for new treatment strategies. Here, we examined the relevance of collecting functional, genomic, and metabolomics data to validate patient-derived models in a hypoxic microenvironment. Methods: From our biobank of...

BACKGROUND Integrin α5β1 was suggested to be involved in glioblastoma (GBM) aggressiveness through preclinical studies and genomic analysis of several cohorts of patients. However, protein expression data are still missing to confirm this hypothesis. Our aim was to investigate the prognostic value of integrin α5 protein expression level in GBM. MA...

BACKGROUND Glioblastoma (GBM) is the most aggressive primary brain tumor. Treatment failure and recurrence are explained in part by tumoral heterogeneity. Our previous results showed that the integrin α5β1 is implicated in GBM aggressiveness and represents a relevant therapeutic target. Recently, we observed intra- and inter-tumor heterogeneity of...

e13552 Background: BRAF V600E mutation is encountered in brain tumor, mostly low grade pediatric diffuse glioma (LGG) and epileptogenic glioneuronal tumor such as gangliogliomas (GG) or pleomorphic xanthoastrocytomas (PXA). Less frequently this mutation is present in high grade glial or glioneuronal tumors such as pleomorphic xanthoastrocytomas wit...

11014 Background: The survival of pediatric OS is stable worldwide since two decades. The management of OS is lacking new approaches to classify closely the patients and adapt thereafter the treatments. The objectives of our molecular study, using allelotyping, quantitative PCR (qPCR) and droplet digital PCR (ddPCR), were to determine the survival...

Integrins contribute to cancer progression and aggressiveness by activating intracellular signal transduction pathways and transducing mechanical tension forces. Remarkably, these adhesion receptors share common signaling networks with receptor tyrosine kinases (RTKs) and support their oncogenic activity, thereby promoting cancer cell proliferation...

Nucleic acid aptamers are often referred to as chemical antibodies. Because they possess several advantages, like their smaller size, temperature stability, ease of chemical modification, lack of immunogenicity and toxicity, and lower cost of production, aptamers are promising tools for clinical applications. Aptamers against cell surface protein b...

Gliomas are the most common type of pediatric brain tumors. One third of them are high grade gliomas (pHGG) with a significant dismal prognosis and a very poor therapeutic arsenal. So, new therapeutic ideas are needed to counterpart the high resistance to current treatments. Therefore, our team focused recently on the glutaminolysis switch, which w...

Children diagnosed for brain tumors are facing variant prognoses depending mostly on the histological subtypes and their molecular characteristics. Nevertheless, more and more evidence is accumulating on the diffuse infiltrative growth pattern of the tumor, playing its own role in tumor development and progression. This infiltration is reflecting t...

Gliomas are the most common type of pediatric brain tumors. Most of them are low grades, but one third are high grade gliomas (pHGG) with a significant impact on patients’ median survival, which is averaging 1 year depending on mutational background. Despite the progress in their molecular knowledge, we need to understand their development and rapi...

Introduction Overexpression of epidermal growth factor (EGFR) drives glioblastoma (GBM) cell invasion and tumour progression. EGFR has been a major therapeutic target in GBM. However, clinical trials were disappointing, and we are still missing molecular basis to explain these poor results. In other solid tumours, extracellular matrix proteins foun...

Basal cell carcinoma (BCC) is the most frequent human cancer and is becoming an important health problem in an ageing population. Based on their clinical and histological characteristics, thick BCC are typically divided into low-risk nodular and high-risk infiltrative subtypes, although the underlying mechanisms are poorly understood. We have ident...

Aptamers are nucleic acids referred to as chemical antibodies as they bind to their specific targets with high affinity and selectivity. They are selected via an iterative process known as 'selective evolution of ligands by exponential enrichment' (SELEX). Aptamers have been developed against numerous cancer targets and among them, many tumor cell-...

Children diagnosed for pHGGs, comprising mostly tumors of the brain midline (brainstem and thalamic locations), are facing with a very dismal prognosis. Those brain cancers are bearing usually and in more than 80% of the cases the histone H3.3 mutations. Up to now, the only therapy improving transiently the outcome of those children is irradiation....

The Wnt/beta catenin pathway has been highlighted as an important player of brain tumors aggressiveness and resistance to therapies. Increasing knowledges of the regulation of beta-catenin transactivation point out its hub position in different pathophysiological outcomes in glioma such as survival and migration. Crosstalks between integrins and be...

Development of novel anticancer formulations is a priority challenge in biomedicine. However, in vitro models based on monolayer cultures (2D) which are currently used for cytotoxicity tests leave much to be desired. More and more attention is focusing on 3D in vitro systems which can better mimic solid tumors. The aim of the study was to develop a...

Using two models of cell migration, we showed that α5 integrin is involved in glioblastoma cell resistance to anti-EGFR drugs. Simultaneous targeting α5 and EGFR help to inhibit cell motility and may represent a promising approach to sensitize a5 expressing cells. Afatinib may be more efficient than reversible TKI EGFR in a5 expressing cells, which...

Integrins belong to a large family of αβ heterodimeric transmembrane proteins first recognized as adhesion molecules that bind to dedicated elements of the extracellular matrix and also to other surrounding cells. As important sensors of the cell microenvironment, they regulate numerous signaling pathways in response to structural variations of the...

Distant metastases arise in 20-30% of patients with squamous cell carcinoma of the head and neck (HNSCC) in the 2 years following treatment. Therapeutic options are limited and the outcome of the patients is poor. The identification of predictive biomarkers of patient at risk for distant metastasis and therapies are urgently needed. We previously i...

Integrin α5β1 expression is correlated with a worse prognosis in high-grade glioma. We previously unraveled a negative crosstalk between integrin α5β1 and p53 pathway, which was proposed to be part of the resistance of glioblastoma to chemotherapies. The restoration of p53 tumor-suppressor function is under intensive investigations for cancer thera...

The activity of synthetic interfering nucleic acids (siRNAs) relies on the capacity of delivery systems to efficiently transport nucleic acids into the cytosol of target cells. The pyridylthiourea-grafted 25 KDa polyethylenimine (πPEI) is an excellent carrier for siRNA delivery into cells and it was extensively investigated in this report. Quantifi...

Integrins are transmembrane heterodimeric proteins sensing the cell microenvironment and modulating numerous signalling pathways. Changes in integrin expression between normal and tumoral cells support involvement of specific integrins in tumor progression and aggressiveness. This review highlights the current knowledge about α5β1 integrin, also ca...

Glioblastoma is the most common malignant primary brain tumor. Surgical resection, postoperative radiotherapy plus concomitant and adjuvant chemotherapy with temozolomide (TMZ) is the standard of care for newly diagnosed glioblastoma. In the past decade, efforts have been made to decipher genomic and core pathway alterations to identify clinically...

Caveolin-1 plays a crucial role in the development of cancer and its progression. We previously reported that glioblastoma cells expressing low levels of caveolin-1 exerted a more aggressive phenotype than cells expressing high levels. Such phenotype was due to the induction of α(5) β(1) integrin subsequent to the depletion of caveolin-1. Caveolin-...

Methylated analogues of imidazoline related compounds (IRC) were prepared; their abilities to bind I-1 imidazoline receptors (I(1)Rs), I-2 imidazoline binding sites (I2BS) and alpha(2)-adrenoceptor subtypes (alpha(2)ARs) were assessed. Methylation of the heterocyclic moiety of IRC resulted in a significant loss of alpha(2)AR affinity. Amongst the s...

Integrins play a role in the resistance of advanced cancers to radiotherapy and chemotherapy. In this study, we show that high expression of the α5 integrin subunit compromises temozolomide-induced tumor suppressor p53 activity in human glioblastoma cells. We found that depletion of the α5 integrin subunit increased p53 activity and temozolomide se...

Success of synthetic interfering nucleic acids (siRNAs)-based therapy relies almost exclusively on effective, safe and preferably nanometric delivery systems which can be easily prepared, even at high concentrations. We prepared by chemical synthesis various self-assembling polymers to entrap siRNAs into stable polyplexes outside cells but with a d...

The α5β1 integrin represent a new therapeutic target for glioblastoma, which are malignant brain tumors difficult to cure with conventional therapies. Glioblastoma are known to be highly resistant to chemotherapy. We, therefore, investigated whether blocking α5β1 integrin with specific nonpeptidic antagonists concomitantly with chemotherapy (ellipt...

Herein, using a recently developed hydration-sensitive ratiometric biomembrane probe based on 3-hydroxyflavone (F2N12S) that binds selectively to the outer leaflet of plasma membranes, we compared plasma membranes of living cells and lipid vesicles as model membranes. Through the spectroscopic analysis of the probe response, we characterized the me...

Ellipticine is a potent antineoplastic agent exhibiting multiple mechanisms of action with promising brain tumor specificity. This anticancer agent should be considered a pro-drug, whose pharmacological efficiency and/or genotoxic side effects are dependent on its cytochrome P450 (CYP) - and/or peroxidase-mediated activation to species forming cova...

Progress in the design of gene delivery systems is of utmost importance for cancer gene therapy since several physiological and intracellular barriers remain. We previously developed a technology for condensing a single gene into a single and stable globular nanometric system. In this manuscript, we have decorated the nanometric particles with cycl...

Caveolin-1 plays a checkpoint function in the regulation of processes often altered in cancer. Although increased expression of caveolin-1 seems to be the norm in the glioma family of malignancies, populations of caveolin-1 positive and negative cells coexist among glioblastoma specimens. As no data are available to date on the contribution of such...

The hypotensive effect of imidazoline-like drugs, such as clonidine, was first attributed to the exclusive stimulation of central α2-adrenoceptors (α2ARs). However, a body of evidence suggests that non-adrenergic mechanisms may also account for this hypotension. This work aims (i) to check whether imidazoline-like drugs with no α2-adrenergic agonis...

Gliomas are the most common deadly brain tumors. Human cerebral tumors express high level of alpha5beta1 integrins. As a potential new target, alpha5beta1 was investigated here in two human astrocytoma cell lines, A172 and U87MG. We found that a hypersialylated beta1 integrin was endogenously expressed in A172 cells. It forms heterodimers with alph...

The potential role of alpha5beta1 integrins in cancer has recently attracted much interest. However, few alpha5beta1-selective antagonists have been developed compared with other integrins. The most specific nonpeptidic alpha5beta1 antagonist described thus far, SJ749, inhibits angiogenesis by affecting adhesion and migration of endothelial cells....

One of the major tyrosine phosphorylation activities linked to integrin signalling is that of focal adhesion kinase (FAK). High amounts of FAK are located at specialised subcellular compartments known as focal adhesions. FAK tyrosine phosphorylation at focal adhesions is increased by various stimuli including integrin engagement during migration pr...

Binding affinities at I 1 and I 2 Imidazoline Binding Sites (IBS) of a number of properly substituted imidazoline, oxazoline and pyrroline ligands were studied through an integrated modelling approach based on a coordinated application of 2D- (MGZ) and 3D-QSAR (CoMFA-and GRID-GOLPE) analyses and on the development of a quantitative pharmacophore (H...