The nanomechanical signature of breast cancer

Abstract

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.

Periductal stromal collagen topology of pancreatic ductal adenocarcinoma differs from that of normal and chronic pancreatitis

“…Collagen is the preeminent scaffolding element in the human body, and alignment and cross-linking have been shown to increase tumor tissue stiffness levels. 53,54 Cells, in turn, are able to sense changes in the mechanical properties of the local environment and respond to them in ways that deviate from behaviors under normal tissue homeostasis. 55,56 Therapeutic targeting of lysyl oxidase in mouse models has shown promise in reducing collagen cross-linking and tumor stiffness, and ultimately in reversing the malignant phenotypes of cells.…”

The extracellular matrix in breast cancer predicts prognosis through composition, splicing, and crosslinking

“…The microarchitecture of the fibrilar collagen network (typically collagen I) in the stroma is believed to play a major role in specifying both risk of BC and the stiffness of the stromal ECM [37,50,54,55], suggesting that stiff stroma could encourage tumor initiation or progression. Depending on species, age and testing method, breast interstitial ECM has been measured to have a modulus of 167731 Pa [35], 0.4 kPa [37] and 1.13 70.78 kPa [55], and the risk of developing BC has been linked to increases in total breast stiffness both clinically [54].…”

Toward correlating structure and mechanics of platelets

“…34 Interestingly, normal, benign and malignant tissues were shown to exhibit different mechanical properties enabling a future possibility of applications in clinical diagnostics. 35 A change in the material properties is bound to arise from a change in the macromolecular structures of a tissue or a cell. However, to understand the direct influence of macromolecular re-modeling of a cell in different states and its relation to the mechanical properties, a direct correlation between the mechanical properties of a cell and its structure is important.…”