Catégorie d'actualités: significant publications

Breast cancer: towards early diagnosis by imaging

In vivo imaging of metastatic breast cancer tumors at very early stages is about to become possible. A team of chemists and biologists from the Center for Molecular Biophysics (CNRS) has indeed developed a new magnetic resonance imaging (MRI) probe which has a selective affinity for an emerging biomarker of metastatic breast cancer: Netrin- 1. Find out more on the Cnrs Chimie website.

See more and Cnrs Chmie website.

Reference
Peptide-Conjugated MRI Probe Targeted to Netrin-1, a Novel Metastatic Breast Cancer Biomarker
Clémentine Moreau, Tea Lukačević, Agnès Pallier, Julien Sobilo, Samia Aci-Sèche, Norbert Garnier, Sandra Même, Éva Tóth & Sara Lacerda
Bioconjugate Chemistry 2024
https://doi.org/10.1021/acs.bioconjchem.3c00558

Watching enzymes work in vivo with rare-earth-based molecular probes

Scientists at the CNRS Centre de Biophysique Moléculaire (CBM) in Orléans and the Institut de Chimie des Substances Naturelles (CNRS/Université Paris-Saclay) have designed luminescent probes. They are based on complexes of lanthanides (Ln), a series of rare-earth metals whose trivalent Ln3+ ions are luminescent. The special feature of these probes is that the activity of certain enzymes can modify their luminescence in the near infrared, as well as the signal observed on MRI. These probes make it possible to track the catalytic activity of an enzyme with a single molecule using several complementary imaging techniques: MRI and near-infrared optics. Essential for unambiguous detection of a biological phenomenon, this dual imaging with a single molecule avoids biases due to the use of chemically different imaging agents for each imaging technique.

This study, published in the journal Angewandte Chemie International Edition, paves the way for new non-invasive diagnostic strategies.

This work has been reported on the Cnrs Chimie website

Article reference
Lanthanide-Based Probes for Imaging Detection of Enzyme Activities by NIR Luminescence, T1- and ParaCEST MRI
Rémy Jouclas, Sophie Laine, Svetlana V. Eliseeva, Jérémie Mandel, Frédéric Szeremeta, Pascal Retailleau, Jiefang He, Jean-Francois Gallard, Agnès Pallier, Célia S. Bonnet, Stéphane Petoud, Philippe Durand & Éva Tóth
Angew. Chem. Int. Ed. 2024
https://onlinelibrary.wiley.com/doi/10.1002/anie.202317728

The study of terrestrial fossils in ancient rocks: a crucial approach to identify potential signs of life on Mars

The NASA Perseverance rover is actively exploring Jezero Crater, analyzing igneous and sedimentary rocks from the crater floor and delta deposits. The rock samples that will be returned by the Mars Sample Return (MSR) mission in the 2030s will be subjected to detailed laboratory studies.

Some samples may contain traces of ancient Martian life, which are challenging to detect due to their morphological simplicity and subtle geochemical expressions. Using volcanic sediments from Kitty’s Gap Chert (Pilbara, Australia) of 3.45 billion years as analogues, researchers detail the steps needed to demonstrate their syngenicity and biogenicity. Various analytical methods, including optical and electron microscopy, Raman spectroscopy, X-ray fluorescence spectroscopy, and mass spectrometry, have been employed at different scales. Sedimentological, petrological, mineralogical, and geochemical analyses document a coastal environment of deposition, consistent with the development of microbial life. Morphological, elemental, and molecular analyses of carbonaceous matter associated with potential fossil remnants reveal enrichment in bioessential trace metals (V, Cr, Fe, Co, etc.) and colocalized aromatic and aliphatic molecules of biological origin. This study illustrates the analytical protocol necessary to optimize the detection of fossil traces of life in Martian rocks.

This work is reported on the CNRS Chimie website

Reference
Multi-Technique Characterization of 3.45 Ga Microfossils on Earth: A Key Approach to Detect Possible Traces of Life in Returned Samples from Mars
Laura Clodoré, Frédéric Foucher, Keyron Hickman-Lewis, Stéphanie Sorieul, Jean Jouve, Matthieu Réfrégiers, Guillaume Collet, Stéphane Petoud, Bernard Gratuze, Frances Westall
Astrobiology 2024
http://doi.org/10.1089/ast.2023.0089

Enzymatic detection in near infrared optical imaging and MRI with a single ligand complexed to different lanthanide ions

The imaging visualization of active enzymes is of primary importance in biology.

In a collaborative effort between the Centre of Molecular Biophysics (CBM) and the Institute of Chemistry of Natural Substances (ICSN) in Gif sur Yvette, CBM researchers have designed Ln3+ complexes that provide enzyme-mediated changes in NIR luminescence, as well as in Chemical Exchange Saturation Transfer (CEST) and classical T1-weighted MRI, depending on the Ln3+ used. They have demonstrated the successful monitoring of b-galactosidase activity over time in NIR luminescence and CEST MR imaging in phantoms containing the Yb-complex, and in T1 MRI when using the Gd-analogue. A further great advantage of their probe design is its high versatility, as there are a large number of enzymatically cleavable groups that could be attached to the same core, thus creating probes for other important enzyme targets.

Reference : Rémy Jouclas, Sophie Laine, Svetlana V. Eliseeva, Jérémie Mandel, Frédéric Szeremeta, Pascal Retailleau, Jiefang He, Jean-Francois Gallard, Agnès Pallier, Célia S. Bonnet, Stéphane Petoud, Philippe Durand, Éva Tóth
Lanthanide-Based Probes for Imaging Detection of Enzyme Activities by NIR Luminescence, T1- and ParaCEST MRI
Angew. Chem. Int. Ed. 2024, https://onlinelibrary.wiley.com/doi/10.1002/anie.202317728

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