New biomarkers in inflammation, fibrosis and cancer imaging (LBI)
Team Van Beers
Department Hepato-Gastroenterology Department
Laboratory of imaging biomarkers – LBI
We perform translational research in medical imaging to develop and validate novel imaging biomarkers in inflammation, fibrosis and cancer. Our efforts range from fundamental research in imaging methods to applied preclinical and clinical research in hepatic and abdominal diseases.
We improve rapid, functional and quantitative methods at magnetic resonance imaging (MRI) (diffusion MRI, perfusion MRI, MR elastography, susceptibility and relaxometry) and ultrasound imaging. We also assess novel tracers for cellular imaging. These developments are first validated on thin tissue sections and in small animals. Once the proofs of concept are obtained, the methods are transferred to clinical imaging.
Our LBI laboratory participates in the imaging research network “France Life Imaging”, with Philippe Garteiser acting as coordinator of the Paris Centre hub. Our laboratory is also active within the Université de Paris “Imageries du Vivant” network. In addition, the LBI laboratory is one of the two imaging research teams in charge of the preclinical imaging platform “FRIM” (Inserm UMS34).
Main research projects
Imaging of hepatic inflammation in metabolic diseases
Non-invasive assessment of inflammation and hepatocyte injury is important to diagnose non-alcoholic steatohepatitis or NASH. The RHU “QUID-NASH” project that we pursue with other academic and industrial partners aims to assess new non-invasive imaging methods of NASH in murine models of steatohepatitis and in a cohort of 600 diabetic patients with biopsy-proven hepatic steatosis. We develop a virtual hepatic biopsy approach, integrating multi-omic data and quantitative parameters obtained with ultrafast ultrasound, multiparametric MRI and MR elastography. Recently, we have launched a study on the frequency dispersion of the diffusion coefficient in hepatic tissue (ANR funded “Stedi-NASH”). The proposed method enables to probe hepatic tissue at specific spatial scales. This novel method has the potential to inform hepatocyte size and cytoplasmic content.
Steatosis (left) and hepatic stiffness (right) maps in a patient graded S1A1F1 at histopathology (top row) and a patient graded S2A3F3 (bottom row).
Imaging of the forces in hepatic cancer
To provide advanced characterization of tumor mechanical properties, the apparent elasticity at different levels of static load can be measured. We use this compression MR elastography method to assess tumor interstitial pressure and solid stress, two parameters playing a role in the efficiency of targeted treatments (H2020 European project “FORCE”).
Elasticity maps of patient-derived hepatocarcinoma xenografted in nude mouse, measured at different levels of static load, showing increase in apparent elasticity under load (Pagé G et al. J Magn Reson Imaging 2019, Pagé G et al. Cancers 2021)
Functional contrast-enhanced MRI of the liver
Pharmacokinetics of hepatospecific agents
Hepatocyte influx, biliary efflux and sinusoidal backflux can be assessed with pharmacokinetic modelling after dynamic liver MRI with hepatospecific contrast agents (Gd-EOB-DTPA, Primovist). Similarly to most drugs, those hepatospecific agents cross the hepatocyte membranes through specific transporters, including OATPs, MRP2 and MRP3, creating concentration gradients between the extracellular compartment, the hepatocytes and the biliary compartment.
The hepatocyte uptake of hepatospecific contrast agents (Gd-EOB-DTPA) is performed through OATP membrane transporters. MRP2 is responsible for biliary efflux, and MRP3 for sinusoidal back-flux. The amount and function of these transporters are modified in chronic liver diseases (Van Beers BE et al. J Hepatol 2012)
Liver perfusion and transport through the hepatocytes are important determinants of hepatic function. Using dynamic hepatobiliary contrast-enhanced MRI and developing pharmacokinetic modelling, we study the changes of the transport parameters in murine models of chronic liver disease as well as patients. Our aim is to use MRI pharmacokinetic parameters as biomarkers of liver function, since they reflect the alteration of quantity and functionality of hepatic transporters (OATPs, MRP2 and MRP3).
Parametric maps obtained with hepatobiliary contrast-enhanced MRI, showing modifications of hepatic transport parameters in a patient diagnosed with hepatic cirrhosis (bottom) compared to a patient without hepatic fibrosis (top) (Ronot M, Joly F, Van Beers BE in Seiberlich N et al. Quantitative magnetic resonance imaging, Elsevier 2020)
Macrophage-based contrast agents in fibrogenesis
The dynamics of fibrogenesis and fibrolysis has been seldom studied with biomedical imaging. Using dedicated MRI acquisition sequences and intravenous injections of ultrasmall iron oxide particles (USPIO), we observe the different macrophage populations involved in this dynamic process, according to their endocytic capacity.
Assessment of R2 (a), R2* (b), R2’ (c) relaxation rates and magnetic susceptibility (d) show that pro-inflammatory M1 macrophages exhibit higher MRI parameters than M0 and M2 macrophages, because of higher USPIO concentrations within the former. This increased uptake in M1 macrophages is confirmed at immunofluorescence (right panels) (Khaled W et al. J Magn Reson Imaging 2019)
MRI of liver cirrhosis and portal hypertension
Classically, the assessment of cirrhosis and portal hypertension severity relies on hepatic venous pressure gradient measurements. We have shown that MR elastography provides a non-invasive method for assessing portal hypertension severity (Ronot M et al. Eur Radiol 2014). We aim to improve this approach by integrating MR elastography data with radiomic information and biological data extracted from microcirculating vesicles (IFB project “Integrative bioinformatics”).
Parametric maps showing increase in hepatic (top) and splenic (bottom) shear modulus according to portal hypertension severity (A and D: hepatic venous pressure gradient below 10 mmHg; B and E: pressure gradient between 10 and 11 mmHg; C and F: pressure gradient above 11 mmHg) (Van Beers BE et al. Semin Liv Dis 2017)
Pancreatic quantitative MRI in obesity
We observed that pancreatic tissue in obesity could be characterized before and after bariatric surgery with quantitative MRI, including the measurements of the mechanical properties, fat fraction and R2* relaxation rate. We are currently developing a similar approach in the ANR project “PAIR-pancréas” to detect the pre-tumoral pancreatic lesions associated with the metabolic syndrome.
Elasticity (left), fat fraction (middle) and R2* relaxation rate (right) in the pancreas of control rats, obese rats and obese rats after bariatric surgery. Obesity induces an increase in MRI parameters, which is partially reversed after bariatric surgery. Histological analysis of pancreatic tissue confirms these observations (Rebours V, Garteiser P et al. Sci Rep 2018)
Quantitative MRI of intestinal inflammation and fibrosis
In a rat model of radiation-induced colitis, we observe that combining MRI parameters of signal intensity, perfusion, diffusion and magnetization transfer is useful for assessing inflammation and fibrosis, with potential therapeutic implications (Zappa M et al. NMR Biomed 2018).
Advanced methods for MRI data analysis
Our team also works on the extraction of quantitative data from MR images and parametric maps. We develop radiomic-based as well as unsupervised methods to extract those quantitative data. The integration of the ever-increasing volume of quantitative data generates new challenges for statistical analysis. Therefore, we develop innovative regularized multi bloc approaches for dimension reduction of highly multidimensional data.
If you want to join our team as post-doc, PhD or master student, please contact us: [mailto:email@example.com]
Publication date : 01 April 2021 More
Tumor Solid Stress: Assessment with MR Elastography under Compression of Patient-Derived Hepatocellular Carcinomas and Cholangiocarcinomas Xenografted in Mice Cancers (Basel).
Autors : Page Gwenael Marion Tardieu Jean-Luc Gennisson Laurent Besret Garteiser Philippe Van Beers Bernard
Publication date : 01 April 2020 More
Quantification of hepatic steatosis with ultrasound: promising role of attenuation imaging coefficient in a biopsy-proven cohort Eur Radiol.
Autors : Dioguardi Burgio Marco Ronot Maxime Edouard Reizine Rautou Pierre-Emmanuel Castera Laurent Paradis Valérie Garteiser Philippe Van Beers Bernard Vilgrain Valérie
Publication date : 01 April 2020 More
Comparison of pulsed and oscillating gradient diffusion-weighted MRI for characterizing hepatocellular nodules in liver cirrhosis: ex vivo study in a rat model J Magn Reson Imaging.
Autors : Mathilde Wagner Doblas Sabrina Poté Nicolas Simon A Lambert Ronot Maxime Garteiser Philippe Paradis Valérie Vilgrain Valérie Van Beers Bernard
Publication date : 14 May 2019 More
Assessing Tumor Mechanics by MR Elastography at Different Strain Levels J Magn Reson Imaging
Autors : Page Gwenael Tardieu M Besret L Blot L Lopes J Sinkus R Van Beers Bernard Garteiser Philippe
Publication date : 01 April 2019 More
In vitro distinction between proinflammatory and antiinflammatory macrophages with gadolinium-liposomes and ultrasmall superparamagnetic iron oxide particles at 3.0T J Magn Reson Imaging
Autors : Khaled W Piraquive J Leporq B Wan Jinghong Lambert SA Mignet N Doan BT Lotersztajn Sophie Garteiser Philippe Van Beers Bernard
Publication date : 02 November 2018 More
Obesity-induced pancreatopathy in rats is reversible after bariatric surgery Sci Rep
Autors : Rebours Vinciane Garteiser Philippe Ribeiro-Parenti Lara Cavin JB Doblas Sabrina Page Gwenael Bado André Couvineau Alain Ruszniewski Philippe Paradis Valérie Le Gall Maude Van Beers Bernard Couvelard Anne
Publication date : 01 April 2018 More
Quantitative MRI in murine radiation-induced rectocolitis: comparison with histopathological inflammation score. NMR Biomed.
Autors : Zappa Magaly Doblas Sabrina Cazals-Hatem Dominique Milliat F Lavigne J Daniel F Jallane Abdelhak Garteiser Philippe Vilgrain Valérie Ogier-Denis Eric Van Beers Bernard
Publication date : 01 August 2017 More
Quantitative Imaging in Diffuse Liver Diseases Semin Liver Dis
Autors : Van Beers Bernard Garteiser Philippe Leporq B Rautou Pierre-Emmanuel Valla Dominique
Publication date : 28 April 2017 More
Hepatic Fibrosis, Inflammation, and Steatosis: Influence on the MR Viscoelastic and Diffusion Parameters in Patients with Chronic Liver Disease Radiology
Autors : Leitão HS Doblas Sabrina Garteiser Philippe d'Assignies G Paradis Valérie Mouri F Geraldes CF Ronot Maxime Van Beers Bernard
Publication date : 01 August 2016 More
Hepatic fat fraction and visceral adipose tissue fatty acid composition in mice: Quantification with 7.0T MRI Magn Reson Med
Autors : Leporq B Lambert SA Ronot Maxime Boucenna I Colinart P Cauchy F Vilgrain Valérie Paradis Valérie Van Beers Bernard
Publication date : 01 February 2015 More
Advanced fibrosis: correlation between pharmacokinetic parameters at dynamic gadoxetate-enhanced MR imaging and hepatocyte organic anion transporter expression in rat liver Radiology
Autors : Lagadec M Doblas Sabrina Giraudeau C Ronot Maxime Lambert SA Fasseu M Paradis Valérie Moreau Richard Pastor CM Vilgrain Valérie Daire Jean-Luc Van Beers Bernard