Dynamically softened substrate regulates malignancy of breast tumor cells

Programming temporal stiffness cues within extracellular matrix hydrogels for modelling cancer niches

“…The temporal dynamic stiffening achieved in one of the formulations resulted in the growth arrest of spheroids and a maintenance of metabolic activity after 14 days, which contradicts many studies demonstrating greater cell proliferation in stiffer hydrogels [ 17 , 62 , 65 ]. However, unlike previous static mechanical models [ 58 , 64 , 68 , 69 ], the gradual material stiffening achieved in the 0.5% AdECM/2% silk composition resulted in distinct phenotypic changes which may be more reflective of the heterogeneity of physiological tumours. The breast cancer spheroids self-organised into organised tumouroids with acinar-like structures as seen in breast epithelium in vivo [ 11 , 125 ].…”

“…This model establishes intra-tumoural heterogeneity and the instatement of EMT programs within luminal MCF-7 breast cancer cells in response to temporal ECM changes. While stimuli-responsive biomaterials have been developed for tumour modelling which undergo matrix softening and stiffening, those models are static, do not represent the scale of ECM stiffening and require addition of external stimuli to incite the mechanical transition [ 58 , 64 , 68 , 69 ]. This new composite biomaterial formulation does not require external stimuli to undergo progressive stiffening and represents a greater range of compressive moduli than previous studies.…”

“…To study the effects of static ECM mechanics on disease progression in in vitro models, most studies focus on tuning the initial hydrogel properties to achieve distinct hydrogels of variable static stiffness (through modulating the density of polymer or number of crosslinks formed), and then transferring cells between matrices or comparing cellular phenotype in side-by-side hydrogels [ 13 , 31 , [58] , [59] , [60] , [61] , [62] , [63] , [64] ]. Early work utilised hydrogel systems to understand the effect of matrix stiffness on integrin adhesions, cellular organisation and growth patterns [ 65 ].…”

Engineering approaches for understanding mechanical memory in cancer metastasis

“…Notably, investigations using dynamically softening hydrogels have also revealed intriguing interdisciplinary findings. Culture on substrates that are dynamically softened by matrix metalloproteinases not only facilitates the storage of mechanical memory, but also results in a weaker malignant potential when cells are transferred to stiffer surfaces ( Hu et al , 2021 ). This study implies that by directly targeting stiffness at the primary tumor, we can leverage the storage of mechanical memory by cancer cells even when they later experience a stiffer mechanical environment.…”

Reprogramming of the Genome-Wide DNA Methylation Landscape in Three-Dimensional Cancer Cell Cultures

“…Stowers and collaborators also proposed using reconstructed basal membrane matrices with Type I collagen and alginate as systems in which the rigidity of the extracellular matrix can be adjusted. It is important to note that more rigid matrices have resulted in cellular morphologies and malignant phenotypes in breast, liver, pancreas, lung, and brain cancers compared with less rigid matrices [ 35 , 36 ]. Thus, it has been reported that improvements in the rigidity of the extracellular matrix can exacerbate traits such as cell migration and invasion, reflecting significant changes in the epigenetic landscape, especially in DNA methylation.…”