The nanomechanical fingerprint of colorectal-derived peritoneal metastasis

Peritoneal metastases (PM) are one of the most common routes of dissemination for colorectal cancer (CRC) and remain a lethal disease with a poor prognosis. The compositional, mechanical and structural properties of the extracellular matrix (ECM) play an important role in cancer development; studying how these properties change during the progression of the disease is crucial to understand CRC-PM development. The elastic properties of ECMs derived from human samples of normal and neoplastic PM in different pathological conditions were studied by atomic force microscopy (AFM); results were correlated to patients clinical data and to the expression of ECM components related to metastatic spread. Our results show that PM progression is accompanied by stiffening of ECM as a common feature; spatially resolved mechanical analysis highlighted significant spatial heterogeneity of the elastic properties of both normal and neoplastic ECMs, which show significant overlap in the two conditions. On the micrometre scale, ECMs that are considered normal according to the pathological classification possess stiffer spatial domains, which are typically associated with cancer associated fibroblasts (CAF) activity and tumour development in neoplastic matrices; on the other hand, softer regions are found in neoplastic ECMs on the same scales. Our results support the hypothesis that local changes (stiffening) in the normal ECM can create the ground for growth and spread from the tumour of invading metastatic cells. Mechanical changes correlate well with the presence of CAF and an increase in collagen deposition, which are well known markers of cancer progression. Furthermore, we have found correlations between the mechanical properties of the ECM and patients clinical data like age, sex, presence of mutations in BRAF and KRAS genes and tumour grade. Overall, our findings suggest that the mechanical phenotyping of the PM-ECM has the potential for predicting tumour development.