Engineering Systems to Study Cancer Metastasis.

[摘要] Metastasis causes most late relapses and fatalities from cancer.Investigating mechanisms of metastasis and designing therapies to limit metastatic disease are challenging due to difficulties studying key events that occur before clinical detection, frequently involving small numbers of cells and intercellular interactions within three metastatic compartments (primary tumor, intravascular, and metastatic sites).By combining microfluidic, tissue engineering, and molecular imaging tools to screen therapies and analyze individual steps of metastasis, we further bridge the physiological gap between standard in vitro models, animal models, and human disease.Firstly, we model how multiple cell types form and respond to chemotactic gradients that drive cell migration in a primary tumor.Using microfluidic tools to robustly pattern chemokine CXCL12 secreting cells, CXCR7+ cells that scavenge this chemokine, and CXCR4+ cells that migrate towards resulting gradients, we performed sensitivity analysis to identify functional combinations that are refractory to therapeutic inhibition.We found one high-matrix binding isoform (CXCL12-γ) to robustly promote chemotaxis even at low chemokine levels in the absence of scavenging cells and in the presence of a clinically approved inhibitor.Linking these findings to clinical physiology, we found this high-matrix-binding isoform to only be expressed in late stage breast cancer.Secondly, we combine tissue engineering and molecular imaging tools to study the response of cancer cells in 3D tissue spheroids.We designed a platform to facilitate handling and high resolution imaging of 384 well spheroids.Using this platform we developed a bone marrow spheroid model to recreate breast cancer quiescence and resistance to therapies.Using dual-colored bioluminescence imaging we simultaneously measured response of quiescent cancer and bone stromal cells to standard cytotoxic and targeted therapies.Using this strategy we identified therapeutic combinations that selectively eliminated quiescent cancer cells in vitro and entirely eliminated bone marrow metastases in mice.We also used this system to visualize metabolic gradients in bone marrow spheroids and measure cancer and stromal response to metabolic perturbations.Combining microfluidic, tissue engineering, and molecular imaging tools as described herein can improve development of better models that recreate in vivo physiology and allow development of patient-specific therapies that prevent or eliminate metastatic disease.

[发布机构] University of Michigan

[效力级别] Tissue engineering

[关键词] Cancer metastasis;Tissue engineering;Chemotaxis;Molecular imaging;Biomedical Engineering;Engineering;Health Sciences;Science;Biomedical Engineering