0000000000198984
AUTHOR
Jessica Gobbo
Tracking the evolution of circulating exosomal-PD-L1 to monitor melanoma patients
ABSTRACT In the era of immunotherapies there is an urgent need to implement the use of circulating biomarkers in clinical practice to facilitate personalized therapy and to predict treatment response. We conducted a prospective study to evaluate the usefulness of circulating exosomal-PD-L1 in melanoma patients’ follow-up. We studied the dynamics of exosomal-PD-L1 from 100 melanoma patients by using an enzyme-linked immunosorbent assay. We found that PD-L1 was secreted through exosomes by melanoma cells. Exosomes carrying PD-L1 had immunosuppressive properties since they were as efficient as the cancer cell from which they derive at inhibiting T-cell activation. In plasma from melanoma patie…
PD-L1 dans les exosomes circulants de patients atteints de mélanome : un nouveau biomarqueur ?
Le pronostic des patients atteints de melanome avance s’est considerablement ameliore depuis l’avenement des therapies ciblees et des immunotherapies. Cependant, tous les patients ne beneficient pas de ces traitements (tts) a cause de resistances primaires ou acquises. Il apparait donc indispensable de developper des biomarqueurs permettant de selectionner les patients potentiellement repondeurs aux tts, d’evaluer precocement l’efficacite de ces tts et diagnostiquer precocement la recidive de la maladie. Nous avons evalue l’interet du dosage de PD-L1 dans les exosomes circulants de patients atteints de melanome avance. Cent patients suivis entre novembre 2016 et janvier 2019 etaient inclus.…
C-terminal amino acids are essential for human heat shock protein 70 dimerization
The human inducible heat shock protein 70 (hHsp70), which is involved in several major pathologies, including neurodegenerative disorders and cancer, is a key molecular chaperone and contributes to the proper protein folding and maintenance of a large number of protein structures. Despite its role in disease, the current structural knowledge of hHsp70 is almost exclusively based on its Escherichia coli homolog, DnaK, even though these two proteins only share ~50 % amino acid identity. For the first time, we describe a complete heterologous production and purification strategy that allowed us to obtain a large amount of soluble, full-length, and non-tagged hHsp70. The protein displayed both …
Quantification of HSP27 and HSP70 Molecular Chaperone Activities
Stress-inducible heat-shock proteins (HSPs, like HSP70 and HSP27) are molecular chaperones that -protect cells from stress damage by keeping cellular proteins in a folding competent state and preventing them from irreversible aggregation. HSP27 and HSP70 chaperone activities are useful indicators to test chemical products and physical stress impact on protein denaturation, to select HSP inhibitors, or to -determine the implication of the chaperone function in other HSP activities, such as apoptosis. We have developed two simple and fast chaperone activity tests for HSP27 and HSP70 that we initially set up to test the effect of potential HSP inhibitors obtained after screening of chemical an…
HSP70 inhibition : a new therapeutic target against cancer
Heat shock proteins (HSPs) were first discovered in Drosophila by Ritossa in 1962. As stress proteins, HSPs are induced in response to a wide variety of physiological and environmental insults. HSPs have a cyto-protective function and act as molecular chaperones by assisting the folding of nascent or misfolded proteins and by preventing their aggregation. Mammalian HSPs have been classified into 5 families according to their molecular weight: HSP110, HSP90, HSP70, HSP60 and the family of small HSPs such as HSP27 (Kampinga et al., 2009). The most well-known inducible stress chaperone HSP70 is hardly detectable at basal level in normal “non-stressed” cells, but in cancer cells HSP70 is consti…
Structural determinants of resveratrol for cell proliferation inhibition potency: experimental and docking studies of new analogs.
International audience; Resveratrol is the subject of intense research because of the abundance of this compound in the human diet and as one of the most valuable natural chemopreventive agents. Further advances require new resveratrol analogs be used to identify the structural determinants of resveratrol for the inhibition potency of cell proliferation by comparing experimental and docking studies. Therefore, we synthesized new trans/(E)- and cis/(Z)-resveratrol - analogs not reported to date - by modifying the hydroxylation pattern of resveratrol and a double bond geometry. We included them in a larger panel of 14 molecules, including (Z)-3,5,4'-trimethoxystilbene, the most powerful molec…
Nanofitins targeting heat shock protein 110: an innovative immunotherapeutic modality in cancer.
The presence of an inactivating heat shock protein 110 (HSP110) mutation in colorectal cancers has been correlated with an excellent prognosis and with the ability of HSP110 to favor the formation of tolerogenic (M2-like) macrophages. These clinical and experimental results suggest a potentially powerful new strategy against colorectal cancer: the inhibition of HSP110. In this work, as an alternative to neutralizing antibodies, Nanofitins (scaffold ~7 kDa proteins) targeting HSP110 were isolated from the screening of a synthetic Nanofitin library, and their capacity to bind (immunoprecipitation, biolayer interferometry) and to inhibit HSP110 was analyzed in vitro and in vivo. Three Nanofiti…
Exosomal HSP70 for Monitoring of Frontotemporal Dementia and Alzheimer’s Disease: Clinical and FDG-PET Correlation
We aimed to study the expression of circulating heat-shock protein HSP70 and exosomes in plasma of a cohort of patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) at different stages. We performed correlations with clinical scales and FDG-PET. HSP70 levels were higher within exosomes than free in plasma. Moderate correlations were found between exosomal HSP70 and CDR, FTLD-CDR, and extension of hypometabolism. Our results suggest modifications in the level of exosomal HSP70 during the course of neurodegeneration, regardless of AD or FTD, and therefore HSP70 could have a potential role in the follow-up of these disorders.
Membrane-anchored heat-shock protein 70 (Hsp70) in cancer.
International audience; Hsp70 is a highly conserved and inducible heat shock protein that belongs to the HSP70 family of molecular chaperones and plays a central role in protein homeostasis. The main function of Hsp70 is to protect cells from physiological, pathological and environmental insults, as it assists an ATP-dependent manner the process of protein folding. Since Hsp70 provides critical cell survival functions, cancer cells are assumed to rely on this chaperone. Strong evidence suggests that Hsp70 is upregulated in different type of cancers and is involved in tumor growth, invasion, migration and resistance to anti-cancer therapy. Interestingly, this Hsp70 upregulation induces Hsp70…
Membrane-bound exosomal HSP70 as a biomarker for detection and monitoring of malignant solid tumours: a pilot study
Abstract Background Cancer is the second leading cause of death globally. Early detection and disease management lead to a better survival rate. Consequently, discovery of novel methods in cancer early diagnosis is a field of active research. Minimally invasive liquid biopsies are generating growing interest. Circulating tumour cells (CTCs) have been identified in patients’ blood; nevertheless, these cells are rare and heterogeneous. Exosomes are extracellular nanovesicles released into the extracellular environment via the endosomal vesicle pathway and found in different body fluids. Exosomes deliver bioactive cargo such as proteins, mRNA and miRNA to recipient cells in the tumour environm…
Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis
Heat shock proteins (HSPs) are necessary for cancer cell survival. We identified a mutant of HSP110 (HSP110ΔE9) in colorectal cancer showing microsatellite instability (MSI CRC), generated from an aberrantly spliced mRNA and lacking the HSP110 substrate-binding domain. This mutant was expressed at variable levels in almost all MSI CRC cell lines and primary tumors tested. HSP110ΔE9 impaired both the normal cellular localization of HSP110 and its interaction with other HSPs, thus abrogating the chaperone activity and antiapoptotic function of HSP110 in a dominant-negative manner. HSP110ΔE9 overexpression caused the sensitization of cells to anticancer agents such as oxaliplatin and 5-fluorou…
Suivi du taux de PD-L1 dans les exosomes pour évaluer la réponse tumorale dans le mélanome
Introduction Le pronostic des patients atteints de melanome avance s’est considerablement ameliore depuis l’avenement des therapies ciblees et des immunotherapies. Cependant, tous les patients ne beneficient pas de ces traitements a cause de resistances primaires ou acquises. Il apparait donc indispensable de developper des biomarqueurs permettant de selectionner les patients potentiellement repondeurs et permettant de surveiller l’efficacite des traitements. Nous avons evalue l’interet du dosage de PD-L1 dans les exosomes circulants de patients atteints de melanome avance. Materiel et methodes Cent patients suivis entre novembre 2016 et janvier 2019 etaient inclus. Les exosomes etaient iso…
Targeting cancer with peptide aptamers
Renaud Seigneuric 1,2 , Jessica Gobbo 1,2 , Pierre Colas 3 , Carmen Garrido 1,2 1 Heat Shock Proteins and Cancer, INSERM, UMR 866 IFR 100, Faculty of Medicine, 7 Boulevard Jeanne D'Arc, 21000 Dijon, France 2 Universite de Bourgogne, Dijon, France 3 CNRS USR 3151, P2I2 Group, Station Biologique, Roscoff, Bretagne, France Received: June 22, 2011; Accepted: June 24, 2011; Published: June 24, 2011; Correspondence: Renaud Seigneuric, email: // // Abstract A major endeavour in cancer chemotherapy is to develop agents that specifically target a biomolecule of interest. There are two main classes of targeting agents: small molecules and biologics. Among biologics (e.g.: antibodies), DNA, RNA but al…
Exosomes in cancer theranostic: Diamonds in the rough
IF 3.306; International audience; During the last 10 years, exosomes, which are small vesicles of 50-200 nm diameter of endosomal origin, have aroused a great interest in the scientific and clinical community for their roles in intercellular communication in almost all physiological and pathological processes. Most cells can potentially release these nanovesicles that share with the parent cell a similar lipid bilayer with transmembrane proteins and a panel of enclosed soluble proteins such as heat shock proteins and genetic material, thus acting as potential nanoshuttles of biomarkers. Exosomes surface proteins allow their targeting and capture by recipient cells, while the exosomes' conte…