Investigating the Mechanisms of Cancer Metastasis through Novel In Vitro and In Vivo Models

Abstract

Cancer is the second highest cause of death globally. In an estimated 90% of all cases, the spread of cancer cells from the initial tumor to a distant site—aka metastasis—is the primary cause of death. Efforts to develop a metastasis-targeting therapy have been faced with frequent failure in clinical trials despite strong preclinical evidence. This discrepancy is largely the result of inadequate models for capturing the complexities of metastasis. In this thesis work, two novel platforms for evaluating metastatic disease were developed. In one platform, progressively invasive subpopulations of metastatic breast cancer were isolated using xenografted zebrafish embryos and characterized to identify two candidate gene targets whose knockdown can significantly reduce invasive spread. In the other platform, circulating tumor cell (CTC) isolation from whole blood based on cell density produced consistent and robust patient-derived CTC cultures and CTC-derived xenografts (CDXs) in immunocompromised mice. For a subset of these cultures and CDXs, transcriptomic and mutational profiling provided insight into possible metastasis biomarkers. Together, this work provides evidence highlighting potential drivers—both previously known as well as new candidates—of cancer metastasis. In the future, these platforms could be critical to the development of metastasis-targeting therapies as robust models of patient-derived metastasis in personalized medicine.