Modeling metastatic invasion of healthy tissue by circulating tumor cells in 3D artificial extracellular matrix hosting biological material

Post-doctoral allowance, 18 months, AAP 2017-1

Team :  LCMCP

Project leader : Francisco Fernandes

Abstract :

The molecular mechanisms of tumor metastasis remain largely unknown and undefined. One of the major challenges that public health and medical research are facing is the ability to find new biomarkers able to anticipate early primary tumor detection as well as tumor insidious dissemination. In this context, one of the major concerns is the ability of cells released out of the primary tumor mass to undergo epithelial-to-mesenchymal transition, generating circulating tumor cells (CTCs). Among these, only a small subset of CTCs is capable of successful metastasis and thus should bear cancer stem cell features such as high invasiveness. These cells are termed circulating cancer stem cells (CSCs).

It is now well recognized that CSCs are essential for tumorigenicity, metastasis and resistance to current therapeutic protocols including radiotherapy. Among biological cues that influence CTC to CSC transition such as oxygen gradients or other chemo-attractants derived from niche sites, extracellular vesicles (micro vesicles and exosomes) seem to participate in cancer genesis and the metastatic process. These vesicles are true signaling compartments which participate in the regulation of a large number of cells and biological transduction pathways. They shuttle between tissues and circulating cells and allow CTCs to exchange cell surface and cytosolic biomarkers with other cells. Further understanding of the heterogeneous set of CTCs sub-populations can provide an invaluable tool to early cancer diagnosis with a dramatic impact on the patients’ outcome. Moreover, it can be used to monitor treatment response by allowing stratification of patients based on their ability to respond to treatment, or used as prognostic marker of primary tumor reseeding or cancer recurrence.

The main hurdle in the study of CTCs and CSCs is, aside their low quantity available in circulating blood, their poor capacity to grow in classical 2D in vitro systems. In such conditions of culture, the molecular architecture of a physiological environment is missing for promoting cell differentiation and proliferation under mechanic stimuli.

In MatriXtasis we propose to use freeze-casting, a technique enabling a precise structuration of biopolymer matrices in non denaturating conditions, to develop a macroporous 3D tissue model able to mimic healthy tissue both in its structure and composition. The proposed biomaterial will act as a platform for the study of tumorigenesis induced by CTCs, and in particular the factors influencing their conversion to CSCs.