Theses Doctoral

The effect of matrix stiffness, composition, and three-dimensionality on p53 expression in engineered human bone tumors

Liu, Zen

Approximately 40% of men and women in the United States will be diagnosed with at least one form of cancer in their lifetime, with cancer being implicated in one in four deaths. While great strides have been made in early diagnosis and treatment using standard regimens of chemotherapy and radiation, resulting in an overall decrease in cancer mortality, tumor initiation, growth and metastasis continue to evade control. The continued search for effective and targeted drugs has been hindered by the high failure rate of costly clinical trials, highlighting a need for more accurate preclinical models of disease, not only for pharmaceutical testing, but also biological research and assay development.
The dominant role of the tumor microenvironment in regulating tumor initiation, progression, and metastasis has been well documented, driving the application of tissue engineering strategies in cancer biology. In vitro models that recapitulate clinically-relevant features of native tumors with greater fidelity than monolayer tissue cultures have the potential to yield discovery of novel therapeutic targets and regimens while also providing critical insights into mechanisms of tumor resistance. This thesis describes a tissue engineering strategy for generating an in vitro tumor model of human conventional chondrosarcoma using a custom biomimetic scaffold, and characterizes the effect of the biomaterial on cancer cell phenotype. Together with a previously validated and published in vitro model of human Ewing’s sarcoma tumors, we further investigated the effect of microenvironmental factors including matrix stiffness, niche composition, and three-dimensionality on the expression of a key cell cycle regulator and tumor suppressor mutated or lost in a wide variety of cancers, p53. A transcription factor nicknamed the “guardian of the genome,” p53 is activated in normal tissues in response to stress and triggers cellular responses including cell cycle arrest and apoptosis, or induces transcription of DNA repair enzymes to promote cell survival. The unifying hypothesis of this thesis was that the tumor microenvironment does in fact influence expression of tumor suppressors like p53, ultimately contributing to the progression of tumors toward metastasis and chemoresistance, and that these effects can be probed in vitro using disease-specific engineered tumor models to identify novel druggable targets and biomarkers with prognostic significance.


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More About This Work

Academic Units
Biomedical Engineering
Thesis Advisors
Vunjak-Novakovic, Gordana
Ph.D., Columbia University
Published Here
October 27, 2017