Hydrogeelipohjaiset 3D-kasvatusalustat rintasyövän mallintamiseen

Breast cancer is a significant cause of cancer-related death in women. To develop more targeted therapies for advanced breast cancer, a detailed knowledge of mechanisms involved in breast cancer progression is required. Hydrogel-based 3D culture systems are particularly promising models for studying microenvironment-regulated changes in cellular phenotypes during metastasis. This thesis compiles three publications that investigated how cells can be guided to model prometastatic phenotypes by tailoring the properties of biopolymer-based hydrogel scaffolds. In Publication I, fibrin gels were used to study the interaction between fibrin and circulating tumor cell (CTC)-like cells representing triple negative breast cancer (TNBC). The phenotypes observed in fibrin gels were clearly distinct from those in Matrigel and suspension culture, evidenced by differences in gene and protein expression and cell morphology. By varying fibrin concentration and degradation rate, the association between fibrin stiffness and the regulation of cellular protrusions was revealed. In addition to cancer cells, immunosuppressive immune cells are associated with poor prognosis in breast cancer. In Publications II and III, plant-derived nanofibrillar cellulose (NFC) gels were used as the hydrogel scaffolds. In Publication II, unmodified NFC gels with varying stiffnesses were used for breast cancer patient-derived explant culture (PDEC). It was discovered that soft matrix influenced the balance of T cells and promoted macrophage polarization to M2-like phenotype through the fibroblast growth factor 2 (FGF2) secreted by the cancer cells. Publication III investigated the immunomodulatory effects of NFC chemical modifications on primary immune cells. NFC surface chemistry was found to influence the gene expression profiles of peripheral blood mononuclear cells (PBMCs) and the differentiation of monocytes to M2-like macrophages. Notably, macrophages generated in phosphorylated NFC gel expressed M2 marker CD206 at similar levels as M2a macrophages differentiated with interleukin-4 (IL-4) treatment in conventional 2D culture. Moreover, the cytokine profile was differentially modulated in cells in phosphorylated NFC gel compared to cells in 2D culture. In conclusion, diverse prometastatic phenomena were recapitulated in the hydrogel-based 3D culture models developed in this thesis. Importantly, the models expanded the phenotypes captured by the 2D culture setup and the commercial Matrigel matrix. These findings contribute to the development of more versatile breast cancer models, which may lead to the discovery of novel treatment modalities to prevent and treat metastatic disease.