Abstract B44: Modeling plasticity of metastasis in vivo using patient-derived xenografts

Specific suppression of metastatic disease is an urgent unmet therapeutic need. Many clinical studies have tried but failed to identify genetic driver mutations specific to metastatic nodules, suggesting that biologic differences between primary and metastatic tumors are driven by reversible mechanisms that enable plasticity of metastasizing cancer cells. The biologic complexity of metastatic colonization and lack of adequate experimental models has limited our knowledge of the molecular regulation of metastasis. An improved understanding of the mechanistic determinants is required for prevention and treatment of metastatic cancer. We have previously established a clinically relevant patient-derived xenograft (PDX) model of melanoma metastasis to compare biologic differences between primary and metastatic tumors. This model recapitulates in mice the metastatic behavior of individual patient tumors. It allows isolation of human melanoma cells from distinct steps of the metastatic cascade for molecular and functional characterization. We have used this model to functionally dissect the metastatic cascade in vivo into distinct steps and quantitatively test the ability of melanoma cells to survive and colonize distant organs at different stages of metastasis. The frequency of circulating tumor cells in the blood of the mice with subcutaneous tumors is used to assess the ability of the cells to intravasate and survive in circulation. The total metastatic burden measured by bioluminescence in all the organs gives a quantitative measure of the ability of the cells to extravasate, seed, and colonize distant organs. Finally, intravenous transplantation removes the barrier of intravasation and is used to only focus on the survival of cancer cells in the blood and extravasation into distant organs, while intrasplenic transplantation models the final step of the metastatic cascade—the ability of the cells to seed and colonize distant organs. Using a combination of these different transplantation methods and limiting dilution analysis, we have shown that metastasizing cancer cells undergo functional and reversible adaptations to their site of growth. Molecular characterization of these adaptations has identified reversible metabolic and transcriptional regulators of metastatic plasticity and the role of the microenvironment in regulating their activity. We have now expanded our work to model pancreatic cancer metastasis using patient-derived tumors. We have shown that pancreatic tumors from different patients display different patterns of metastasis to different vital organs and that metastatic colonization by these tumors is different depending on the site of the primary transplantation site. This work highlights the potential of PDX models of metastasis to recapitulate the clinical outcome of the disease, including latency after seeding and metastatic tropism, which has both therapeutic and diagnostic value. Citation Format: Elena Piskounova. Modeling plasticity of metastasis in vivo using patient-derived xenografts [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B44.