Cyril Corbet

BackgroundNeoadjuvant chemotherapy (NAC) is the standard of care for patients with early-stage triple negative breast cancers (TNBC). However, more than half of TNBC patients do not achieve a pathological complete response (pCR) after NAC, and residual cancer burden (RCB) is associated with dismal long-term prognosis. Understanding the mechanisms underlying differential treatment outcomes is therefore critical to limit RCB and improve NAC efficiency.MethodsHuman TNBC cell lines and patient-derived organoids were used in combination with real-time metabolic assays to evaluate the effect of NAC (paclitaxel and epirubicin) on tumor cell metabolism, in particular glycolysis. Diagnostic biopsies (pre-NAC) from patients with early TNBC were analyzed by bulk RNA-sequencing to evaluate the predictive value of a glycolysis-related gene signature.ResultsPaclitaxel induced a consistent metabolic switch …

Tumor acidosis is associated with increased invasiveness and drug resistance. Here, we take an unbiased approach to identify vulnerabilities of acid-exposed cancer cells by combining pH-dependent flow cytometry cell sorting from 3D colorectal tumor spheroids and transcriptomic profiling. Besides metabolic rewiring, we identify an increase in tetraploid cell frequency and DNA damage response as consistent hallmarks of acid-exposed cancer cells, supported by the activation of ATM and ATR signaling pathways. We find that regardless of the cell replication error status, both ATM and ATR inhibitors exert preferential growth inhibitory effects on acid-exposed cancer cells. The efficacy of a combination of these drugs with 5-FU is further documented in 3D spheroids as well as in patient-derived colorectal tumor organoids. These data position tumor acidosis as a revelator of the therapeutic potential of DNA repair …

Simple Summary Radiotherapy is a cornerstone for the treatment of colorectal cancer. Tumor cells present in an environment lacking oxygen (hypoxia) are resistant, leading to patient relapse. Altering redox homeostasis and inducing cell death of hypoxic cancer cells is a promising strategy to overcome radioresistance. In this study, redox homeostasis was targeted, and cell death (ferroptosis) was induced in colorectal cancer cells by treating them with the FDA-approved drug sulfasalazine. Overall, sulfasalazine treatment improved the response to radiotherapy in a model system of human colorectal cancer cells. Abstract xCT overexpression in cancer cells has been linked to tumor growth, metastasis and treatment resistance. Sulfasalazine (SSZ), an FDA-approved drug for the treatment of rheumatoid sarthritis, and inflammatory bowel diseases, has anticancer properties via inhibition of xCT, leading to the disruption of redox homeostasis. Since reactive oxygen species (ROS) are pivotal for the efficacy of radiotherapy (RT), elevated levels of ROS are associated with improved RT outcomes. In this study, the influence of SSZ treatment on the radiosensitivity of human colorectal cancer (CRC) cells was investigated. Our principal finding in human HCT116 and DLD-1 cells was that SSZ enhances the radiosensitivity of hypoxic CRC cells but does not alter the intrinsic radiosensitivity. The radiosensitizing effect was attributed to the depletion of glutathione and thioredoxin reductase levels. In turn, the reduction leads to excessive levels of ROS, increased DNA damage, and ferroptosis induction. Confirmation of these …

Aim: Acquired resistance to the targeted agent cetuximab poses a significant challenge in finding effective anti-cancer treatments for head and neck squamous cell carcinoma (HNSCC). To accurately study novel combination treatments, suitable preclinical mouse models for cetuximab resistance are key yet currently limited. This study aimed to optimize an acquired cetuximab-resistant mouse model, with preservation of the innate immunity, ensuring intact antibody-dependent cellular cytotoxicity (ADCC) functionality.Methods: Cetuximab-sensitive and acquired-resistant HNSCC cell lines, generated in vitro, were subcutaneously engrafted in Rag2 knock-out (KO), BALB/c Nude and CB17 Scid mice with/without Matrigel or Geltrex. Once tumor growth was established, mice were intraperitoneally injected twice a week with cetuximab for a maximum of 3 weeks. In addition, immunohistochemistry was used to evaluate …

Identification of new biomarkers to better predict and improve response to neoadjuvant chemotherapy in triple negative breast cancers | DIAL.pr - BOREAL Skip to main content User menu Cart Login Home DIAL.pr - BOREAL Search form Search Home All Publications Export Help You are here Home» Identification of new biomarkers to better predict and improve response to neoadjuvant chemotherapy in triple negative breast cancers Accès à distance ? S'identifier sur le proxy UCLouvain | Saint-Louis Identification of new biomarkers to better predict and improve response to neoadjuvant chemotherapy in triple negative breast cancers Primary tabs view(active tab) attached files FNRS validity download article.pdf Open access PDF 106.95 K Derouane, Françoise [UCL] van Marcke, Cédric [UCL] Berlière, Martine [UCL] Van Bockstal, Mieke [UCL] Mourao, Larissa Corbet, Cyril [UCL] Duhoux, François [UCL] et al. [show …

Colorectal cancer (CRC) ranks as the third most frequently diagnosed cancer, and the limited efficacy of current treatments often leads to frequent relapses. Cetuximab (CTX) stands as the most used anti-EGFR targeted therapy for CRC. Mutation of oncogenes is commonly associated with the development of resistance to CTX. However, patients with CRC classified as "quadruple wild type" (4WT), characterized by the absence of mutations in KRAS, NRAS, BRAF, and PIK3CA, also exhibit a resistance to this therapy. The dependency of cancer cells on glycolysis promotes the initiation and progression of tumors. Methylglyoxal (MG), an inevitable by-product of glycolysis, induces glycation on proteins, lipids and DNA. We have previously shown that the depletion of glyoxalase 1 (GLO1), the main MG detoxifying enzyme, induces an endogenous MG stress that enhances growth and metastatic capacity. We observed that GLO1-depleted CRC cells develop resistance to CTX. This project endeavours to elucidate the molecular mechanisms, driven by MG stress, that lead to the development of CTX resistance in 4WT cells. The use of CRC resistant clones, generated after long term challenge with CTX, let us conclude that MG stress was not a major feature of resistant cells. Therefore, we next focused on the generation of persistent CRC cells, enriched after short challenge with CTX, to better position MG stress during the process of the acquisition of resistance. Persistent cells demonstrated resistance to CTX that was evidenced by a gain in AKT and ERK activation, efficient escape from apoptosis when compared with parental cells. Nevertheless …

BackgroundPathological complete response (pCR) after neoadjuvant chemotherapy (NAC) is known as a prognostic factor correlated with improved EFS and OS. Better prediction of pCR would allow better patient and treatment selection. We aim to reveal specific transcriptomic and metabolic signatures correlated with distinct responses to NAC based on patient diagnostic biopsies. We also compared metabolic profiles of in vitro models.MethodsWe performed bulk-RNA sequencing on 95 samples from diagnostic biopsies from all subtypes of early BC treated with NAC (NCT03314870 study). Early triple-negative BC cell lines (HCC38, HCC1143, HCC1937) and patient-derived tumor organoids were cultured for drug testing, RT-qPCR and metabolomics studies using Seahorse bioenergetic analyzer.ResultsTranscriptomic analyses showed a down-regulation of genes related to tumor cell metabolism such as genes …

Materials and MethodsA549 lung cancer cells cultured in vitro in T25 cm² flasks were irradiated using 220 kV X-rays with either an open, striped (5 mm openings and 10 mm blockings) or dotted (5 mm diameter openings and 18 mm center-to-center distance) fields. Nominal delivered doses (D) were 2, 5 and 10 Gy. Image segmentation was used to locate the centroid of surviving colonies (SCs) in scanned images of the cell flasks. Gafchromic™ film dosimetry (GFD) was employed to map the dose distribution in the flasks at each SC centroid. The paired, co-registered digital images with SCs and radiation dose were divided into 1 mm² quadrats. A modified linear-quadratic (LQ) model was used in a Poisson regression framework to analyze the SC count per quadrat. Here, D and D² where the principal explanatory variables with α and β as fit parameters. In addition, we introduced the nearest distance from the high …

Simple Summary Despite the increased use of neoadjuvant chemotherapy in the early setting of breast cancer, there is a clinical need for predictive markers of response in daily practice. In the era of precision medicine and personalized treatment, new predictive markers that enable the better selection of patients for specific therapies are required. In this review, we describe the current knowledge about the molecular biomarkers used for clinical decision making for patients with breast cancer. We also report how microenvironment-driven intratumoral heterogeneity may influence the validation of biomarkers useful for precision medicine. We provide an overview of promising biomarkers, including pathological markers, genetic signatures, radiological techniques and liquid biopsies, with a great potential to be implemented in routine clinical practice. Finally, we discuss the use of relevant pre-clinical models of breast cancer to integrate microenvironmental specificities in order to identify and validate reliable biomarkers of (non-)response to neoadjuvant chemotherapy. Abstract Pathological complete response (pCR) after neoadjuvant chemotherapy in patients with early breast cancer is correlated with better survival. Meanwhile, an expanding arsenal of post-neoadjuvant treatment strategies have proven beneficial in the absence of pCR, leading to an increased use of neoadjuvant systemic therapy in patients with early breast cancer and the search for predictive biomarkers of response. The better prediction of response to neoadjuvant chemotherapy could enable the escalation or de-escalation of neoadjuvant …

Organoid technologies represent a major breakthrough in biomedical research since they offer increasingly sophisticated models for studying biological mechanisms supporting human development and disease. Organoids are three-dimensional (3D) physiological in vitro systems that recapitulate the genetic, histological and functional features of the in vivo tissues of origin more accurately than classical cell culture methods. In the last decade, organoids have been derived from various healthy and diseased tissues and used for a wide range of applications in basic and translational research, including (cancer) tissue biology, development, regeneration, disease modeling, precision medicine, gene editing, biobanking and drug screening. Here, we report the current applications of organoid models to study (stem) cell metabolism in several pathophysiological contexts such as cancer and metabolic diseases. More precisely, we discuss the relevance and limitations of these 3D cultures to model and study metabolic (dys)functions associated with hepatic, renal or pancreatic disorders, as well as tumor development and progression. We also describe the use of organoids to understand the dynamic interaction between diet, microbiota and the intestinal epithelium. Finally, this review explores recent methodological improvements in organoid culture that may help to better integrate the influence of microenvironmental conditions in the study of tumor cell metabolic phenotypes.

Lung cancer is still the leading cause of cancer-related deaths worldwide (1). Patients with lung cancer feature poor clinical outcomes primarily due to the challenges of early detection, high risk of metastasis and the development of resistance to multiple therapies. Thus, a deeper understanding of the molecular mechanisms supporting therapy escape is essential to improve the survival rate and prognosis of this disease. Currently, international guidelines have established a minimum panel of so-called “must test genes”, including epidermal growth factor receptor (EGFR), Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) and V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) mutations, Anaplastic Lymphoma Receptor Tyrosine Kinase (ALK), ROS Proto-Oncogene 1, Receptor Tyrosine Kinase (ROS1), Rearranged During Transfection (RET), Neurotrophic Receptor Tyrosine Kinase (NTRK) gene rearrangements and MET Proto-Oncogene, Receptor Tyrosine Kinase (MET) exon 14 skipping, for tyrosine kinase inhibitors (TKIs) administration and the evaluation of the expression level of Programmed death-ligand 1 (PD-L1), for immune-checkpoint inhibitors (ICIs) administration, in order to avoid to leave any non-small cell lung cancer (NSCLC) patient behind (2). Beyond well-established biomarkers, others are being currently under investigation as potentially actionable genomic alterations.(Zhou et al.; Zhai et al.)Overall, in this Special Topic of Frontiers in Oncology and Frontiers in Pharmacology, we attempt to address some major concerns related to targeted therapies and ICIs administration, novel therapeutic strategies, resistance …

ORBi: Detailled Reference institution logo Login EN [EN] English [FR] Français logo Login EN [EN] English [FR] Français Give us feedback Explore SearchSpecial collections Statistics News Help Start on ORBiDepositProfilePublication ListAdd your ORCIDTutorialsLegal InformationTraining sessions About What's ORBi ?Impact and visibilityAround ORBiAbout statisticsAbout metricsOAI-PMHORBi teamRelease Notes Back 1.Home 2.Detailled Reference Available on ORBi since 23 May 2023 Poster (Scientific congresses and symposiums) Acquired resistance to Cetuximab in quadruple wild-type colorectal cancer: role of methylglyoxal stress Lardinois, Fanny; Crake, Rebekah; Bellier, Justine et al. 2022 • EACR - European Association for Cancer Research Permalink https://hdl.handle.net/2268/303066 FilesSend toDetailsStatisticsBibliographySimilar publications Files Full Text FL Poster EACR 2022.pdf Author …

BackgroundCD44 is a multifunctional membrane glycoprotein. Through its heparan sulfate chain, CD44 presents growth factors to their receptors. We have shown that CD44 and Tropomyosin kinase A (TrkA) form a complex following nerve growth factor (NGF) induction. Our study aimed to understand how CD44 and TrkA interact and the consequences of inhibiting this interaction regarding the pro-tumoral effect of NGF in breast cancer.MethodsAfter determining which CD44 isoforms (variants) are involved in forming the TrkA/CD44 complex using proximity ligation assays, we investigated the molecular determinants of this interaction. By molecular modeling, we isolated the amino acids involved and confirmed their involvement using mutations. A CD44v3 mimetic peptide was then synthesized to block the TrkA/CD44v3 interaction. The effects of this peptide on the growth, migration and invasion of xenografted triple …

Simple Summary Colorectal cancer is the third most prevalent cancer worldwide. Treatment options for these patients consist of surgery combined with chemotherapy and/or radiotherapy. However, a subset of tumors will not respond to therapy or acquire resistance during the course of the treatment, leading to patient relapse. The interplay between reprogramming cancer metabolism and radiotherapy has become an appealing strategy to improve a patient’s outcome. Due to the overexpression of certain enzymes in a variety of cancer types, including colorectal cancer, the serine synthesis pathway has recently become an attractive metabolic target. We demonstrated that by inhibiting the first enzyme of this pathway, namely phosphoglycerate dehydrogenase (PHGDH), tumor cells that are deprived of oxygen (as is generally the case in solid tumors) respond better to radiation, leading to increased tumor cell killing in an experimental model of human colorectal cancer. Abstract Augmented de novo serine synthesis activity is increasingly apparent in distinct types of cancers and has mainly sparked interest by investigation of phosphoglycerate dehydrogenase (PHGDH). Overexpression of PHGDH has been associated with higher tumor grade, shorter relapse time and decreased overall survival. It is well known that therapeutic outcomes in cancer patients can be improved by reprogramming metabolic pathways in combination with standard treatment options, for example, radiotherapy. In this study, possible metabolic changes related to radioresponse were explored upon PHGDH inhibition. Additionally, we evaluated …

Pharmacological AMPK activation represents an attractive approach for the treatment of type 2 diabetes (T2D). AMPK activation increases skeletal muscle glucose uptake, but there is controversy as to whether AMPK activation also inhibits hepatic glucose production (HGP) and pharmacological AMPK activators can have off-target effects that contribute to their anti-diabetic properties. The main aim was to investigate the effects of 991 and other direct AMPK activators on HGP and determine whether the observed effects were AMPK-dependent. In incubated hepatocytes, 991 substantially decreased gluconeogenesis from lactate, pyruvate and glycerol, but not from other substrates. Hepatocytes from AMPKβ1−/− mice had substantially reduced liver AMPK activity, yet the inhibition of glucose production by 991 persisted. Also, the glucose-lowering effect of 991 was still seen in AMPKβ1−/− mice subjected to an …

Squamous cell carcinoma of the head and neck (SCCHN) is among the most prevalent cancer types worldwide. Despite multimodal therapeutic approaches that include surgical resection, radiation therapy or concurrent chemoradiation, targeted therapy and immunotherapy, SCCHN is still associated with a poor prognosis for patients with locally advanced or recurrent/metastatic (R/M) diseases. Although next-generation sequencing data from thousands of SCCHN patients have provided a comprehensive landscape of the somatic genomic alterations in this disease, genomic-based precision medicine is not implemented yet in routine clinical use since no satisfactory genetic biomarker has been identified for diagnosis, patient outcome prediction and selection of tailored therapeutic options. The lack of significant improvement in SCCHN patient survival over the last decades stresses the need for reliable predictive …

Colorectal cancer (CRC) is the third most common cancer diagnosed and the lack of effectiveness of current therapies leads to frequent relapses. Monoclonal antibodies cetuximab and panitumumab are the most used anti-EGFR targeted therapy in CRC. Genetic alterations, such as activating mutations, are commonly associated with a lack of response to anti-EGFR therapy. Strikingly, patients with CRC diagnosed as "quadruple wild type" (unmutated for KRAS, NRAS, BRAF and PIK3CA) also show a lack of response to this therapy. Reliance of cancer cells on glycolysis promotes tumorigenesis and malignant progression. Methylglyoxal (MG) is an unavoidable glycolytic by-product that glycates proteins, lipids, and DNA. MG stress results from the imbalance between MG production and its enzymatic detoxification by glyoxalase 1 (GLO1). Upon MG stress, cancer cells enhanced their growth and metastatic potential. In our hands, induction of MG stress in quadruple WT cells rendered them resistant to cetuximab. In this project, we aim to explore MG stress-driven molecular mechanisms underlying the acquisition of cetuximab resistance in quadruple WT CRC. Indeed, such resistant tumours could benefit from the targeting of MG stress using potent MG scavengers, such as carnosine and metformin. We have previously shown that LIM1215 human quadruple WT CRC cells undergo a glycolytic switch associated with MG stress upon the acquisition of cetuximab resistance. GLO1-depleted LIM1215 cells showed an increased viability when challenged with cetuximab. Consistently, NOD-SCID mice sub-cutaneously injected with GLO1-depleted LIM1215 …

Extracellular acidification has been shown to be an important characteristic of invasive tumors, as it promotes invasion and migration but also resistance to treatments. Targeting transporters involved in the regulation of tumor pH constitutes a promising anti-tumor approach, as it would disrupt cellular pH homeostasis and negatively impact tumor growth. In this study, we evaluated the impact of syrosingopine, an inhibitor of MCT1 and MCT4, as a modulator of tumor metabolism and extracellular acidification in human breast cancer (MDA-MB-231) and pharyngeal squamous cell carcinoma (FaDu) cell models. In both models in vitro, we observed that exposure to syrosingopine led to a decrease in the extracellular acidification rate, intracellular pH, glucose consumption, lactate secretion and tumor cell proliferation with an increase in the number of late apoptotic/necrotic cells. However, in vivo experiments using the MDA-MB-231 model treated with a daily injection of syrosingopine did not reveal any significant change in extracellular pH (pHe) (as measured using CEST-MRI) or primary tumor growth. Overall, our study suggests that targeting MCT could lead to profound changes in tumor cell metabolism and proliferation, and it warrants further research to identify candidates without off-target effects.

Simple Summary Obesity promotes both development and progression of breast cancer. As a disease, obesity is followed by hyperglycemia, hyperinsulinemia, and hyperlipidemia. The impact of obesity, accumulation of fat depots, and related markers on the metabolism of tumors still remains poorly understood. The aim of this study is to characterize the putative differences in the metabolism of tumors from obese and lean mice. The findings reported here could help tailor personalized treatments targeting tumor metabolism in obese cancer patients by identifying the metabolic preferences of these tumors. Abstract Obesity is characterized by an excessive fat mass accumulation associated with multiple disorders, including impaired glucose homeostasis, altered adipokine levels, and hyperlipidemia. Despite clear associations between tumor progression and obesity, the effects of these disorders on tumor metabolism remain largely unknown. Thus, we studied the metabolic differences between tumors of obese and lean mice in murine models of triple-negative breast cancer (E0771 and PY8819). For this purpose, a real-time hyperpolarized 1-13C-pyruvate-to-lactate conversion was studied before and after glucose administration in fasting mice. This work was completed by U-13C glucose tracing experiments using nuclear magnetic resonance (NMR) spectroscopy, as well as mass spectrometry (MS). Ex vivo analyses included immunostainings of major lipid, glucose, and monocarboxylic acids transporters. On the one hand, we discovered that tumors of obese mice yield higher lactate/pyruvate ratios after glucose …

ORBi: Detailled Reference institution logo Login EN [EN] English [FR] Français logo Login EN [EN] English [FR] Français Give us feedback Explore SearchSpecial collections Statistics News Help Start on ORBiDepositProfilePublication ListAdd your ORCIDTutorialsLegal InformationTraining sessions About What's ORBi ?Impact and visibilityAround ORBiAbout statisticsAbout metricsOAI-PMHORBi teamRelease Notes Back 1.Home 2.Detailled Reference Available on ORBi since 23 May 2023 Poster (Scientific congresses and symposiums) Methylglyoxal Stress and Acquired Resistance to EGFR-Targeted Therapy in Colorectal Cancer Lardinois, Fanny; Crake, Rebekah; Bellier, Justine et al. 2022 • INTERUNIVERSITY PHD STUDENT DAY Permalink https://hdl.handle.net/2268/303067 FilesSend toDetailsStatisticsBibliographySimilar publications Files Full Text FL Poster PhD Day 2022 FINAL.pdf Author postprint (3.38 …