Morphometry and mechanical instability at the onset of epithelial bladder cancer

Malignancies of epithelial tissues, called carcinomas, account for most cancer cases. Research has largely focused on correlating different carcinoma subtypes to genetic alterations. However, as well as a rewiring in the signalling networks, carcinoma progression is accompanied by mechanical changes in the epithelial cells and the extracellular matrix. Here we reveal intricate morphologies in the basement membrane at the onset of bladder cancer and propose that they emerge from a mechanical instability upon epithelial overgrowth. We imaged mouse and human bladder tissue and performed differential growth simulations, and found that stiffness changes in the different mucosa layers can result in aberrant tissue morphologies. The resulting thickening, wrinkles and folds resemble early papillary tumours and carcinomas in situ. Atomic force microscopy confirmed local stiffness changes in the pathological basement membrane. Our findings suggest a possible mechanical origin of the different bladder carcinoma subtypes and may guide future developments in treatment and prophylaxis. Carcinoma subtypes are normally linked to specific genetic alterations, but tissue mechanical changes also play a role. Now, aberrant morphologies resembling bladder carcinoma are shown to emerge from stiffness changes during epithelial overgrowth.