Physics of Cancer

Investigators: Charlotte Rivière, Hélène Delanoe-Ayari, Jean-Paul Rieu

Cancer Stem cells (CSC) niche
Cell Growth and Signaling analysis in response to mechanical constraints

It has been shown that cell behavior is modified under confinement. However, so far the confined walls were made of rigid material, which cannot be deformed by the cells. What happens if the walls are soft enough to be deformed by the confined cells? We want to address this question using “soft microfluidics” approach. We are currently analyzing the effect on cell growth for MultiCellular Tumor Spheroid Model (Fig1. A) and at the single cell level for Cancer Stem Cells (Fig1. B).

Figure 1: Soft Confinement:

(A) MultiCellular Tumor Spheroid confined in a between 2 hydrogel walls where beads are embedded in order to measure Traction forces exerted by the Spheroid during its growth.

(B) Cancer Stem cells confined in a soft confiner system (h=3.5 µm) thanks to pillars made of hydrogels.

Microfluidic-based system to create 3D in-vivo tumor like environment for drug screening

Many drug candidates for cancer treatment show potential when examined in-vitro but fail in clinical trials. This failure may stem at least in part from the use of conventional in-vitro systems that fail to replicate the physiological microenvironment in humans as well as the lack of cell-phenotypic measurements. We propose here two major improvements for in vitro tests: (1) usage of a 3D micro-environment for cells (the Extra Cellular Matrix (ECM) proteins and fibers, together with gradients of soluble factors secreted by cells), (2) the perfusion of drugs at distance from the biological samples.

we are currently quantitatively analysing cancer cell drug-resistance in in-vivo like environment by implementing an agarose-based microfluidic device (Fig. 2) designed to quantitatively and dynamically assess cellular behaviour and the secretion of various interleukins from (i) 3D multicellular tumour spheroids (MCTS), and (ii) biopsies.

Figure 2: Agarose based microfluidics: Spheroids (S) under investigation are enclosed in a central chamber. The porous nature of the agarose gel makes possible to impose solute boundary conditions with concentration C1 and C2 via two side channels and thus control the concentration gradient. Representative images of a spheroid mixed with 2 breast cancer cell lines (MDA-MD231 and MCF7 (red) cell lines) are shown below (left: phase image, middle: merged FITC, RFP channel). Scale Bar: 300 µm. Bottom right: Example of concentration profile along the central channel, obtained by analyzing the fluorescence intensity profile of a fluorescent dye.

Extravasation Biomimetic
Microsystem to unravel cell capacity to deform and pass through pores of defined geometry and stiffness

We  propose  to  elucidate  the  cellular  mechanisms  underlying  one  critical  step  in  tumor progression:  the  endothelial  transmigration.  Indeed,  when  entering  (intravasation)  and  exiting (extravasation)  the  vascular  vessels,  cancer  cells  need  to  transmigrate  across  the  endothelial  layer  of  the blood vessel walls which  stiffness and geometric confinement  creates serious challenges to the cancer cells, requiring them to sustain drastic deformations.

We are currently studying  in vitro the extravasation of colorectal cancer cell lines with different  metastatic  characteristics  in  microsystems  mimicking  blood  vessels  interstices.  To  do  so microfluidic devices implementing networks of micro-pillars and micro-channels were developed  (Figure 3). Two main aspects are varied in order to model the  in vivo environment associated with the endothelial barrier: the pore geometry and the pore stiffness.

To quantify cell ability to extravasate, several  parameters are investigated  such as  typical deformation  undergone by cells, trajectories, transit time  and minimum pore-size that the cells are able to cross.

Figure 3: Microsystems for cancer cell migration analysis:

a) Configuration with arrays of micro-pillars. b) Configuration with micro-channels.


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