Catégorie d'actualités: significant publications

New imaging probe enables MRI detection of early-stage breast cancer tumors

Despite significant progress in cancer imaging and treatment over the years; early diagnosis, metastasis detection, and a better understanding of cancer progression remain an unmet clinical need. Molecular imaging can fulfil this need, but requires the design of contrast agents which target specific tumor biomarkers. Netrin-1 is an extracellular protein overexpressed in metastatic breast, and it is implicated in tumor progression, angiogenesis and appearance of metastasis and tumor aggressivity.

Reserachers of the team "Metal complexes and MRI", develop and validated in vivo the first Netrin-1 specific peptide-based multimodal probe.  A structural validation was performed by molecular docking, thanks to a collaboration CBM and Institute of Organic and Analytical Chemistry.

This probe enabled successful triple-negative metastatic breast tumor visualization namely at early development stage (tumor volume 0-50 mm3), by magnetic resonance imaging (MRI). Such peptide-based probes are molecular platforms allowing imaging by MRI or single photon emission tomography. This bimodal approach makes it possible to scan a wide range of target concentrations (nM to μM), enabling in vivo mapping of Netrin-1 in cancer murine models, at different tumor evolution stages.

References:
Clémentine Moreau, Tea Lukačević, Agnès Pallier, Julien Sobilo, Samia Aci-Sèche, Norbert Garnier, Sandra Même, Éva Tóth and Sara LacerdaPeptide-Conjugated MRI Probe Targeted to Netrin-1, a Novel Metastatic Breast Cancer Biomarker
Bioconjugate Chem. https://doi.org/10.1021/acs.bioconjchem.3c00558

Comprehensive review about the “logic of protein modifications”

Among the main functional building blocks of living cells are proteins, small “molecular machines” produced by the cell according to the information encoded in genes. Each protein has its characteristic chemical composition which defines its structure and function.

In some circumstances, the chemical composition of a protein can be changed in an enzymatic process known as post-translational modification (PTM), whereby additional chemical groups are covalently attached to the protein. PTMs are used by the cell as a regulatory mechanism to control protein function. The addition of new chemical groups – which can come in different shapes and sizes, ranging from small groups, through sugars and lipids, to small proteins – changes the structure and interactions of a protein and can impact almost any aspect of its function.

Marcin Suskiewicz, a structural biologist and biochemist from the CBM, has devoted many years to studying various types of protein PTMs and currently supervises a project devoted to one particular type of PTMs, protein SUMOylation.

In the review published in the journal BioEssays, he reviews the history of the research into protein PTMs as well as various facets of this phenomenon, including the underlying chemical principles, molecular mechanisms, and evolution.

The review combines an introduction to the field with an overview of the recent literature and new ideas and hypotheses.

References:

The logic of protein post-translational modifications (PTMs): Chemistry, mechanisms and evolution of protein regulation through covalent attachments
Marcin Suskiewicz
BioEssays
First published:21 January 2024
https://doi-org.insb.bib.cnrs.fr/10.1002/bies.202300178

Research on glioma (brain tumor) carried out at the CBM highlighted by CNRS Chimie

The use of different original NMR methods (MRI, 1H HR-MAS, 2D liquid NMR) made it possible to characterize a glioma model established in adult Drosophila and to reveal the therapeutic potential of a serotonin receptor for the treatment of these cancers.

Read the CNRS Chimie article.

Read the "Actualité chimique" article n° 492, 2024, February

Gliomas account for 50% of brain cancers and therefore constitute the most common brain tumors. Molecular alterations involved in adult gliomas have been identified and mainly affect tyrosine kinase receptors with amplification and/or mutation of the epidermal growth factor receptor (EGFR) and its associated signaling pathways. Several targeted therapies have been developed but current treatments remain ineffective for glioblastomas, the most severe forms. Thus, it is a priority to identify new pharmacological targets. Here, we used a Drosophila glioma model in adult, to characterize metabolic disturbances associated with glioma and assess the consequences of the serotonin 5-HT7 receptor expression on glioma development. First, by using in vivo Magnetic Resonance Imaging, we have shown that expression of the constitutively active forms of EGFR and PI3K in adult glial cells induced enlargement of brains. Then, we explored altered cellular metabolism by using High-Resolution Magic Angle Spinning NMR and 1H-13C Heteronuclear Single Quantum Coherence solution state. Discriminant metabolites identified highlight rewiring of metabolic pathways in glioma, and associated cachexia phenotypes. Finally, the expression of 5-HT7R in this model attenuates phenotypes associated with glioma development (brain enlargement and cachexia).

Article :
An adult Drosophila glioma model to highlight metabolic dysfunctions and evaluate the role of the serotonin 5-HT7 receptor as a potential therapeutic target.
Bertrand M, Szeremeta F, Hervouet‐Coste N, Sarou-Kanian V, Landon C, Morisset-Lopez S, Decoville M
The FASEB Journal. 2023 37:e23230. doi:10.1096/fj.202300783RR

A review on ADP-ribosylation appeared in the journal Cell

ADP-ribosylation is a biochemical reaction in which the ADP-ribose group from NAD+ becomes covalently attached to various substrates. As such, ADP-ribosylation represents a ubiquitous modification of proteins and other biomolecules (e.g., nucleic acids). Catalysed by a range of specific enzymes, the most important of which in humans is PARP1, ADP-ribosylation serves as a regulatory mechanism influencing a wide array of cellular processes in all domains of life. This new review, published in the authoritative Leading Edge series of reviews of the journal Cell, covers the state of the art on this subject spanning structural biology, biochemistry, cell biology, and the clinical facets of ADP-ribosylation. In addition to Marcin Suskiewicz from the CBM as the first author, the review was co-authored by Ivan Ahel and members of his group at the University of Oxford.

Suskiewicz M., Prokhlrova E., Rack J.G.M., Ahel I.
ADP-ribosylation from molecular mechanisms to therapeutic implications
Cell Review, Volume 186, Issue 21, pages 4475-4495, October 12, 2023 - doi: 10.1016/j.cell.2023.08.03

The work of CBM researchers on the epidermis highlighted by the CNRS Institute of Chemistry

L'Institut de Chimie du CNRS a publié dans sa rubrique "Actualités" un article signalant les recherches sur l'épiderme de l'équipe "Biologie cutanée et microenvironnement", dirigée par le Docteur Catherine Grillon.

Actuellement, les modèles 3D de peau, en culture in vitro, sont développés dans les conditions d’oxygène de l’air ambiant, soit 18 à 20%. Pourtant, à l’intérieur de la peau, le taux d’oxygène physiologique est beaucoup plus bas, notamment dans la couche basale de l’épiderme où il descend entre 1 et 3%. Dans ces conditions les modèles actuels sont-ils véritablement représentatifs de l’état physiologique de notre peau ?

Pour répondre à cette question, les scientifiques de l'équipe "Biologie cutanée et microenvironnement" ont reconstruit de nouveaux modèles 3D d’épiderme respectant le taux réel d’oxygène physiologique dans la peau. Ils ont montré que le taux d’oxygène influe sur l'épaisseur de la peau et qu'il contrôle les défenses antioxydantes des cellules de l'épiderme.

Ce travail démontre qu’il est important de prendre en compte le taux réel d'oxygène physiologique pour comprendre le fonctionnement des cellules de l’épiderme en condition in vitro.

Voir l'actualité sur le site de l'Institut de Chimie du CNRS

Référence

Chettouh-Hammas N, Fasani F, Boileau A, Gosset D, Busco G & Grillon C.
Improvement of Antioxidant Defences in Keratinocytes Grown in Physioxia: Comparison of 2D and 3D Models.
Oxid Med Cell Longev. 2023

https://doi.org/10.1155/2023/6829931

The CNRS Institute of Chemistry reports on its website the work of CBM researchers

Understanding the function of proteins requires knowing their structures.
To do this, scientists used artificial intelligence to predict the shape of a class of "PARP" type proteins that regulate DNA repair, gene transcription, and antiviral response, but are also potential targets for new cancer therapies. This approach, published in the journal Nucleic Acids Research, could be extended to many other families of proteins.

Voir l'actualité sur le site de l'Institut de Chimie du CNRS

Référence

Updated protein domain annotation of the PARP protein family sheds new light on biological function
Marcin J. Suskiewicz, Deeksha Munnur, Øyvind Strømland, Ji-Chun Yang, Laura E. Easton, Chatrin Chatri , Kang Zhu, Domagoj Baretić, Stéphane Goffinont, Marion Schuller, Wing-Fung Wu, Jonathan M Elkins, Dragana Ahel, Sumana Sanyal, David Neuhaus & Ivan Ahel
Journal Nucleic Acids Research

https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkad514/7199335?login=true

Oxygen impact on our skin antioxidant defences: a new epidermis 3D model that is closer to physiology

Skin in vitro 3D models, with varying degrees of complexity, are all developed under ambient air oxygen conditions, i.e. 18-20%, and are widely used to study the mechanisms governing skin functions or to screen numerous molecules for pharmaceutical or cosmetic purposes. However, in the skin, the physiological oxygen level is much lower, particularly in the basal layer of the epidermis where it falls to between 1 and 3%. In in vitro culture, skin cells are therefore in hyperoxia. Are these models representative of the physiological state of our skin?

To investigate this, researchers in the "Skin Biology and Microenvironment" team have developed new 2D and 3D in vitro models under the oxygen conditions of the skin's physiological microenvironment. They have shown that oxygen levels influence keratinocyte proliferation, leading to morphological differences in reconstructed epidermis. As oxygen levels are important in the production of free radicals, molecules that accelerate skin ageing, the researchers studied the antioxidant defences of the cells in these cultures. They showed that antioxidant activity was increased in physiological conditions, either by over-expression or over-activation of enzymes.

This work shows that oxygen levels control the antioxidant defences of skin cells, and that it is important to take this parameter into account in order to reproduce physiological conditions as closely as possible.

Improvement of Antioxidant Defences in Keratinocytes Grown in Physioxia: Comparison of 2D and 3D Models.
Chettouh-Hammas N, Fasani F, Boileau A, Gosset D, Busco G, Grillon C.
Oxid Med Cell Longev. 2023 Jun 17;2023:6829931. doi: https://doi.org/10.1155/2023/6829931