Glioblastoma multiforme (GBM) is an aggressive Grade IV astrocytoma with a poor survival rate. This is largely due to the GBM tumor cells migrating away from the primary tumor site along white matter tracts and blood vessels leading to secondary tumor sites. It is unknown whether the microenvironment nanotopography influences the biomechanical properties of the tumor cells. Although these tumor cells have an innate propensity to migrate, we believe that the nanotopography changes the biomechanical properties to enhance the migratory phenotype. To study this, we used an in vitro polycaprolactone aligned nanofiber film that mimics the nanotopography of the white matter tracts and blood vessels to investigate the mechanical properties of the GBM tumor cells. Our data demonstrate that the cytoskeletal stiffness, traction force, and focal adhesion area are inherently lower in invasive GBM tumor cells compared to healthy astrocytes. Moreover, the tumor cytoskeletal stiffness was significantly reduced when cultured on the aligned nanofiber films compared to smooth and randomly aligned nanofibers films. Analysis of gene expression also showed that tumor cells cultured on the aligned nanotopography upregulated key migratory genes and downregulated key proliferative genes. In addition, cell cycle analysis exhibited a reduced proliferative state on aligned nanofibers, highlighting the dichotomy between proliferation and migration observed in GBM. Finally, focal adhesions of tumor cells were larger and more elliptical when grown on the aligned fibers, suggesting a more migratory state. Therefore, our data demonstrate that the invasive potential is elevated when the tumor cells are cultured on an aligned nanotopography. This in vitro model can further be used to identify the GBM tumor cells’ response in a mimetic in vivo tumor microenvironment and elucidate how the aligned nanotopography transduces into altered gene and protein expression, thus providing a mechanism to target to inhibit the enhanced migratory behavior observed in these cells.

Le Cancer Colo Rectal (CCR) est la deuxième cause de mortalité par cancer dans le monde. Le risque de récidive après traitement curatif atteint 45% pour les stades 3. Une des hypothèses à l’heure actuelle pouvant expliciter le processus métastatique et les récidives est la présence en son sein de cellules « souches », pouvant « initier » le cancer. Notre réflexion s’inscrit dans la continuité des travaux réalisés au sein de notre Laboratoire, intitulés «Stratégies d’isolement et de caractérisation des cellules initiatrices de cancer colorectal», (Mélin et al, 2012). Dans une première partie, notre travail a porté sur l’analyse in vitro de la sensibilité des fractions enrichies en CIC aux différentes molécules de chimiothérapie les plus couramment utilisées en cancérologie colorectale.Puis, dans une deuxième partie, l’analyse des tumeurs obtenues après greffe a été faite ex ovo sur la Membrane Chorio-Allantoïdienne d’embryon de poulet (CAM), modèle facilement manipulable, peu onéreux et très rapide. Ce modèle étant naturellement immunodéprimé, il permet d’obtenir des informations concernant les phénomènes clés de la tumorigénèse et de la néoangiogénèse. Des analyses de la croissance tumorale, de l’histologie (prolifération, apoptose et vascularisation) et des analyses protéiques ont été menées en parallèle. De cette dernière étude, un marqueur particulier la E cadhérine, a été mis en évidence comme témoin indirect d’agressivité. En effet, au sein des tumeurs obtenues à partir de F1 HCT116, fraction himiosensible, l’expression de la E cadhérine est augmentée contrairement aux tumeurs obtenues à partir de F3 WiDr, fraction chimiorésistante, montrant une diminution d’expression de la E cadhérine.Ainsi, dans une troisième partie, sachant qu’un lien entre cellules initiant le cancer et E cadhérine a été mis en évidence, nous nous sommes focalisés sur son expression. Nous avons alors étudié son expression in vitro sur des cellules résistantes au 5 Fluorouracile. Puis, son expression a été étudiée ex vivo au sein de tissus et de sérums de patients opérés de cancer colorectal. / The ColoRectal Cancer (CCR) is the second leading cause of cancer mortality in the world. The risk of recurrence after curative treatment reaches 45% for stages 3. One of the hypotheses currently able to explain the metastatic process and the recurrences is the presence within it of "stem" cells, which can "initiate" the cancer. Our reflection is in line with the work carried out in our Laboratory, entitled "Strategies for the isolation and characterization of cells that initiate colorectal cancer" (Mélin et al, 2012).In the first part, our work focused on in vitro analysis of the sensitivity of fractions enriched in CIC to different chemotherapy molecules most commonly used in colorectal cancer (CRC). Then, in a second part, the analysis of the tumors obtained after transplantation was made ex ovo on Chicken Embryo Chorio-Allantoid Membrane (CAM), an easily manipulated model, inexpensive and very fast. This model provides information on the key phenomena of tumorigenesis and neoangiogenesis. Analyzes of tumor growth, histology (proliferation, apoptosis and vascularization) and protein analyzes were carried out in parallel. From this last study, a particular marker, E cadherin, was highlighted as an indirect link with witness of aggressiveness. Indeed, within the tumors obtained from F1 HCT116, the chemosensitive fraction, the expression of cadherin E was increased in contrast to the tumors obtained from F3 WiDr, chemoresistant fraction, showing a decrease in expression of E cadherin.Thus, in a third part, knowing that a link between cells initiating cancer and E cadherin was highlighted, we focused on its expression. We first studied its expression in vitro on 5 Fluorouracilresistant cells. Its expression was then studied ex vivo in tissues and sera of operated patients of CRC.