Development of acoustic techniques to study the biophysical properties of cell clusters
Circulating tumor cells (CTCs) are cancer cells that leave the primary tumor, enter the bloodstream and finally spread into another tissue. Some of them travel as clusters and have a higher metastatic potential in comparison to single cell. In the bloodstream, these clusters are subjected to high shear rates, they are able to reversibly reorganize and squeeze to travel through narrow capillaries. Nevertheless, their biophysical properties are poorly known, and the adhesion and deformability of CTC clusters have neither been quantified. The project will focus on the development of acoustic force spectroscopy (AFS), an emerging technique that use acoustic forces in a microfluidic channel containing suspended cells to probe several cells in parallel (contrary to other methods that provide limited statistics on single cells). The aim of the project is to extend this technique to CTC clusters, in order to unveil their rheology (Young modulus, adhesion, yield-stress) and predict their behavior in complex hydrodynamic environments.
Acoustic force spectroscopy (AFS), mechanical properties, adhesion, circulating tumor cell (CTC), cell cluster, granular media, suspensions
The CENTURI PhD project will focus on the mechanics and adhesion of circulating tumor cells (CTC) clusters. For this purpose, acoustic force spectroscopy will be adapted and coupled with advanced optical microscopy to enable handling both individual CTC and CTC clusters and to determine the Young's modulus and adhesion properties of these biological systems. The information obtained will be used to model CTC clusters deformation and flow using concepts from granular media and complex suspensions.
Proposed approach (experimental / theoretical / computational)
Acoustic force spectroscopy relies on the trapping of particules or cells contained in a microfluidic chamber by standing acoustic waves. Pulling cells with acoustic waves enable to measure their adhesive properties. Pushing cells towards the surface of the microfluidic channel and measuring the resulting deformation by optical microscopy allows us to determine their viscoelastic properties. The main advantages of this technique are its ability to handle suspended cells (physiologically relevant for circulating cells) and to perform measurements on several cells in parallel. The current set up has been developed to handle microbeads or single cells and will be further developed in the PhD project to allow the manipulation of cell clusters. By combining the theoretical and technological acoustic know-how of the LMA, the biophysical experience of LAI and the expertise of IUSTI on the rheology of dense particulate media, this project aims to provide a new acoustic tool and theoretical framework for quantitative approaches of biological systems.
This project will develop an acoustic technique to measure the biophysical properties of biological samples of clinical interest. Therefore, it is at the crossroad of engineering, physics and biology.
The LAI is developping experimental approaches and applying physical concepts to achieve a quantitative understanding of molecular and cellular mechanics from a fundamental point of view but with an eye on clinical applications. The LMA aims to probe and activate biological cells by ultrasound. It will accompany the acoustic development from a theoretical and practical point of view and will make it possible to benchmark the technology developed with other acoustic techniques. The IUSTI will participate to the modeling aspect of the project, bringing its expertise on dense particulate media to describe the effective rheology of CTCs and predict their behavior in confined hydrodynamic environments.
We are looking for a student with a strong background in physics or engineering and an interest in biophysics. Programming skills will be a plus.
Is this project the continuation of an existing project or an entirely new one? In the case of an existing project, please explain the links between the two projects
The biophysical properties of circulating tumor cells and clusters are also studied in LAI by atomic force microscopy in the context of the ATIP avneir and H2020-MSCA-IF grants currently runnning.
2 to 5 references related to the project
- Sitters, Kamsma, Thalhammer, Ritsch-Marte, Peterman, Wuite, "Acoustic force spectroscopy", Nature Methods, 2015.
- Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, Yu M, Pely A, Engstrom A, Zhu H, Brannigan BW, Kapur R, Stott SL, Shioda T, Ramaswamy S, Ting DT, Lin CP, Toner M, Haber DA and Maheswaran S. “Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis”. Cell. 2014
3 main publications from each PI over the last 5 years
- Valotteau C., Sumbul F., Rico F. High-speed force spectroscopy: microsecond force measurements using ultrashort cantilevers. Biophysical Reviews, 2019, 11 (5), 689-699.
- Vitry P.*, Valotteau C.*, Feuillie C., Bernard S., Alsteens D., Geoghegan J.A., Dufrêne Y.F. Force-induced strengthening of the interaction between Staphylococcus aureus clumping factor B and loricrin, mBio, 2017, 8 (6), e01748-17.
- Valotteau, C., Dumitru, A. C., Lecordier, L., Alsteens, D., Pays, E., Pérez-Morga, D., & Dufrêne, Y. F. (2020). Multiparametric Atomic Force Microscopy Identifies Multiple Structural and Physical Heterogeneities on the Surface of Trypanosoma brucei. ACS omega, 5(33), 20953-20959.
- de Monchy R., Destrempes F., Saha R. K., Cloutier G., Franceschini E., Coherent and incoherent ultrasound backscatter from cell aggregates, J. Acoust. Soc. Amer. 140(3) 2173-2184, 2016
- de Monchy R., Rouyer J., Destrempes F., Chayer B., Cloutier G., Franceschini E., Effective Medium Theory combined with a polydisperse Structure Factor Model for characterizing red blood cell aggregation, J. Acoust. Soc. Amer. 143(4) 2207-2216, 2018
- Franceschini E., Balasse L., Roffino. S., Guillet B., Probe the cellular size distribution from cell samples undergoing cell death, Ultrasound Med. Biol., 45(7) 1787-1798, 2019
- Clavaud C., Bérut A., Metzger B., Forterre Y., Revealing the frictional transition in shear thickening suspensions, PNAS 114, 5147-5152, 2017
- Bérut A., Chauvet H., Legué V., Moulia B., Pouliquen O., Forterre Y., Gravisensors in plant cells behave like an active granular liquid, PNAS 115, 5123-5128, 2018
- Bérut A., Pouliquen O., Forterre Y., Brownian granular flows down heaps, Phys. Rev. Lett. 123, 248005, 2019