ETH Polymer Physics seminar


2009-10-07
10:15 at HCI J 574

The nanomechanical signature of tumorigenic transformation

Marjia Plodinec

University of Basel

Cells within tissues continuously encounter dynamic mechanical challenges to which they respond by remodeling their cytoskeleton. In cancer, these encounters are often altered thereby causing a change in the cellular response. Here we have been employing atomic force microscopy (AFM) which allows for measuring changes in the nanomechanical properties associated with tumorigenic transformation under near-physiological conditions. For example, the local stiffness of a specimen may be determined at high spatial resolution by indenting the specimen surface with the AFM tip and monitoring its deformation. On a nanoscopic level, AFM has been recently used in a clinical setting to probe with high sensitivity cell and cartilage mechanics. To date, AFM has not yet been applied to three-dimensional (3D) cell culture models or intact cancer tissues, which more appropriately represent the in vivo characteristics of the disease. Towards this goal, we have grown normal (wt) Rat2 fibroblasts and a tumorigenic derivative (Rat2sm9) in a 3D tissue culture system to yield spheroids. Structural changes in the cytoskeleton of these cells cultured on a flat support or as 3D spheroids were correlated with differences in their nanomechanical properties. In tumor spheroids we measured a gradual softening from their periphery to the core, whereas wt spheroids exhibited a homogeneous stiffness distribution. Structural and biochemical analyses indicated that the gradual, centripetal softening in tumor spheroids was caused by increasing hypoxia (lack of oxygen) towards the core. Nanomechanical testing of mammary tumors from transgenic mice corroborated these findings. To verify the clinical relevance for human breast carcinomas, we obtained breast biopsies from 25 patients of different age groups and measured their nanomechanical properties under near-physiological conditions. In malignant tumors the stiffness decreased up to 15-fold from the biopsy's periphery to its core, whereas in benign lesions the stiffness appeared similar in all regions. The nanomechanical signature of the different breast carcinomas correlated well with the pathologist's immuno-histological findings. Our long-term goal is to establish nanomechanical properties as a diagnostic marker for mammary carcinomas.


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