Spatial organization acts on cell signaling: how physical force contributes to the development of cancer

Cells constantly encounter physical forces and respond to neighbors and circulating factors by triggering intracellular signaling cascades that in turn affect their behavior. The mechanisms by which cells transduce mechanical signals to downstream biochemical changes are not well understood. In their work, Salaita and coworkers show that the spatial organization of cell surface receptors is crucial for mechanotransduction. Consequently, force modulation that disrupts the mechanochemical coupling may represent a critical step in cancerogenesis

Nanomechanical characterization of living mammary tissues by atomic force microscopy

The mechanical properties of living cells and tissues are important for a variety of functional processes in vivo, including cell adhesion, migration, proliferation and differentiation. Changes in mechano-cellular phenotype, for instance, are associated with cancer progression. Atomic force microscopy (AFM) is an enabling technique that topographically maps and quantifies the mechanical properties of complex biological matter in physiological aqueous environments at the nanometer length scale. Recently we applied AFM to spatially resolve the distribution of nanomechanical stiffness across human breast cancer biopsies in comparison to healthy tissue and benign tumors. This led to the finding that AFM provides quantitative mechano-markers that may have translational significance for the clinical diagnosis of cancer. Here, we provide a comprehensive description of sample preparation methodology, instrumentation, data acquisition and analysis that allows for the quantitative nanomechanical profiling of unadulterated tissue at submicron spatial resolution and nano-Newton (nN) force sensitivity in physiological conditions

The nanomechanical signature of breast cancer

Cancer initiation and progression follow complex molecular and structural changes in the extracellular matrix and cellular architecture of living tissue. However, it remains poorly understood how the transformation from health to malignancy alters the mechanical properties of cells within the tumour microenvironment. Here, we show using an indentation-type atomic force microscope (IT-AFM) that unadulterated human breast biopsies display distinct stiffness profiles. Correlative stiffness maps obtained on normal and benign tissues show uniform stiffness profiles that are characterized by a single distinct peak. In contrast, malignant tissues have a broad distribution resulting from tissue heterogeneity, with a prominent low-stiffness peak representative of cancer cells. Similar findings are seen in specific stages of breast cancer in MMTV-PyMT transgenic mice. Further evidence obtained from the lungs of mice with late-stage tumours shows that migration and metastatic spreading is correlated to the low stiffness of hypoxia-associated cancer cells. Overall, nanomechanical profiling by IT-AFM provides quantitative indicators in the clinical diagnostics of breast cancer with translational significance