Search for: All records

Approximately 90% of breast cancer related mortalities are due to metastasis to distant organs. At the metastatic sites, cancer cells are capable of evading death by exhibiting cellular or mass dormancy. However, the mechanisms involved in attaining dormancy at the metastatic site are not well understood. This is partly due to the lack of experimental models to study metastatic site‐specific interactions, particularly in the context of brain metastatic breast cancer (BMBC). Herein, an in vitro hyaluronic acid (HA) hydrogel‐based model is developed to study mass dormancy in BMBC. HA hydrogels with a stiffness of ≈0.4 kPa are utilized to mimic the brain extracellular matrix. MDA‐MB‐231Br or BT474Br3 BMBC spheroids are prepared and cultured on top of HA hydrogels or in suspension for 7 days. HA hydrogel induced a near mass dormant state in spheroids by achieving a balance between proliferating and dead cells. In contrast, these spheroids displayed growth in suspension cultures. The ratio of %p‐ERK to %p‐p38 positive cells is significantly lower in HA hydrogels compared to suspension cultures. Further, it is demonstrated that hydrogel induced mass dormant state is reversible. Overall, such models provide useful tools to study dormancy in BMBC and could be employed for drug screening.

 

Despite recent advances in breast cancer treatment, drug resistance frequently presents as a challenge, contributing to a higher risk of relapse and decreased overall survival rate. It is now generally recognized that the extracellular matrix and cellular heterogeneity of the tumor microenvironment influences the cancer cells' ultimate fate. Therefore, strategies employed to examine mechanisms of drug resistance must take microenvironmental influences, as well as genetic mutations, into account. This review discusses three‐dimensional (3D) in vitro model systems which incorporate microenvironmental influences to study mechanisms of drug resistance in breast cancer. These bioengineered models include spheroid‐based models, biomaterial‐based models such as polymeric scaffolds and hydrogels, and microfluidic chip‐based models. The advantages of these model systems over traditionally studied two‐dimensional tissue culture polystyrene are examined. Additionally, the applicability of such 3D models for studying the impact of tumor microenvironment signals on drug response and/or resistance is discussed. Finally, the potential of such models for use in the development of strategies to combat drug resistance and determine the most promising treatment regimen is explored.

 

Hyaluronic acid (HA) is a natural polysaccharide and a key component of the extracellular matrix (ECM) in many tissues. Therefore, HA-based biomaterials are extensively utilized to create three dimensional ECM mimics to study cell behaviors in vitro . Specifically, derivatives of HA have been commonly used to fabricate hydrogels with controllable properties. In this review, we discuss the various chemistries employed to fabricate HA-based hydrogels as a tunable matrix to mimic the cancer microenvironment and subsequently study cancer cell behaviors in vitro . These include Michael-addition reactions, photo-crosslinking, carbodiimide chemistry, and Diels–Alder chemistry. The utility of these HA-based hydrogels to examine cancer cell behaviors such as proliferation, migration, and invasion in vitro in various types of cancer are highlighted. Overall, such hydrogels provide a biomimetic material-based platform to probe cell-matrix interactions in cancer cells in vitro and study the mechanisms associated with cancer progression. 

Breast cancer cells can metastasize either as single cells or as clusters to distant organs from the primary tumor site. Cell clusters have been shown to possess higher metastatic potential compared to single cells. The organ microenvironment is critical in regulating the ultimate phenotype, specifically, the dormant versus proliferative phenotypes, of these clusters. In the context of breast cancer brain metastasis (BCBM), tumor cell cluster–organ microenvironment interactions are not well understood, in part, due to the lack of suitable biomimetic in vitro models. To address this need, herein, we report a biomaterial-based model, utilizing hyaluronic acid (HA) hydrogels with varying stiffnesses to mimic the brain microenvironment. Cell spheroids were used to mimic cell clusters. Using 100–10 000 MDA-MB-231Br BCBM cells, six different sizes of cell spheroids were prepared to study the impact of cluster size on dormancy. On soft HA hydrogels (∼0.4 kPa), irrespective of spheroid size, all cell spheroids attained a dormant phenotype, whereas on stiff HA hydrogels (∼4.5 kPa), size dependent switch between the dormant and proliferative phenotypes was noted ( i.e. , proliferative phenotype ≥5000 cell clusters < dormant phenotype), as tested via EdU and Ki67 staining. Furthermore, we demonstrated that the matrix stiffness driven dormancy was reversible. Such biomaterial systems provide useful tools to probe cell cluster–matrix interactions in BCBM.