3D culture platform for the study of cancer biology and drug response
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Cancer is the third leading cause of death worldwide, accounting for almost 13% of all mortalities. In developed countries, when caught early, cancer is very treatable with high success rates for first line treatments. In fact, only about 10% of cancer-related deaths are due to the primary tumor, with the other 90% being caused by metastatic or recurrent neoplasms. These secondary tumors often present with a reduced sensitivity to chemotherapeutic agents, making treatment difficult. Recently, the role of the cell microenvironment in informing tumor drug response has begun to be appreciated. Despite this, we still lack a comprehensive understanding of this relationship, mostly due to the lack of appropriate in vitro models in which to study cancer-matrix interactions. With the goal of providing insight to such behaviors, the presented research seeks to elucidate the following questions: (1) What effect does a 3D ECM have on cancer cell drug response, both at a cell behavior and protein level? (2) Can we promote in vivo-like cell-cell and cell-ECM interactions in a biomimetic 3D environment? (3) Does a collagen-based 3D culture system recapitulate tissue-specific behaviors of tumor cells? And (4) Can we model disease progression by modulating ECM characteristics? The presented research attempts to first establish the value of 3D culture systems as a model for cancer study, and then use this knowledge to develop and validate a novel, biomimetic cancer cell culture platform. In short, cancer cells are grown into large spheroids and then implanted into type 1 collagen gels. Advanced fluorescent microscopy and protein assays are used to assess cell behavior and drug response. Results indicate that by modulating the collagen content of the gels, cell behavior can be directly controlled, and that the resultant cell behavior is consistent with previous in vivo studies that employed a similar microenvironment. Finally, we show that increasing collagen content can be used as a model of breast cancer progression, including developing insights into later stage tumors with invasive properties.
Thesis (Ph.D.)--Boston University