The solid tumor and its surrounding tumor microenvironment (TME) form an intricate dynamical system characterized by both resource and population heterogeneities. It is widely recognized that the spatiotemporal dynamics of the TME contribute to the progression of cancer and the evolution of therapeutic resistance. Nevertheless, realistic in vitro models that recapitulate the fundamental features of the TME are lacking in preclinical biomedical research.
Our goal is to develop and characterize a set of microfluidics-based in vitro technologies based on evolutionary principles in order to study fundamental problems limiting cancer eradication, such as drug resistance, recurrence, or metastasis. Recently, we have developed the death galaxy, or the evolutionary accelerator, an experimental microfluidic platform that establishes a heterogeneous stress landscape over diverse cellular populations. Designed in the form of connected microhabitats based on evolutionary principles, the technology achieves a controllable chemical gradient via static diffusion or flow-based mechanisms. The platform provides means for quantification of long-term cellular dynamics on the time scale of weeks at single-cell resolution through fluorescent microscopy. In particular, our group has identified (see Lin et al. (2019) Clin. Exp. Met. below) and has been studying the emergence of poly-aneuploid cancer cells (PACCs) in the progression of prostate cancer.
- Lin, K. C.*, Sun, Y.*, Torga, G., Sherpa, P., Zhao, Y., Qu, J., ... & Austin, R. H. (2020). An in vitro tumor swamp model of heterogeneous cellular and chemotherapeutic landscapes. Lab on a Chip, 20(14), 2453-2464.
- Lin, K. C., Torga, G., Sun, Y., Pienta, K. J., Sturm, J. C., & Austin, R. H. (2019). Generation of Heterogeneous Drug Gradients Across Cancer Populations on a Microfluidic Evolution Accelerator for Real-Time Observation. JoVE (Journal of Visualized Experiments), (151), e60185.
- Wu, A., Loutherback, K., Lambert, G., Estévez-Salmerón, L., Tlsty, T. D., Austin, R. H., & Sturm, J. C. (2013). Cell motility and drug gradients in the emergence of resistance to chemotherapy. Proceedings of the National Academy of Sciences, 110(40), 16103-16108.
- Zhang, Q., Lambert, G., Liao, D., Kim, H., Robin, K., Tung, C. K., ... & Austin, R. H. (2011). Acceleration of emergence of bacterial antibiotic resistance in connected microenvironments. Science, 333(6050), 1764-1767.
- Lin, K. C., Torga, G., Sun, Y., Axelrod, R., Pienta, K. J., Sturm, J. C., & Austin, R. H. (2019). The role of heterogeneous environment and docetaxel gradient in the emergence of polyploid, mesenchymal and resistant prostate cancer cells. Clinical & experimental metastasis, 36(2), 97-108.
- Lin, K. C., Torga, G., Wu, A., Rabinowitz, J. D., Murray, W. J., Sturm, J. C., ... & Austin, R. (2017). Epithelial and mesenchymal prostate cancer cell population dynamics on a complex drug landscape. Convergent science physical oncology, 3(4), 045001.
- Han, J., Jun, Y., Kim, S. H., Hoang, H. H., Jung, Y., Kim, S., ... & Park, S. (2016). Rapid emergence and mechanisms of resistance by U87 glioblastoma cells to doxorubicin in an in vitro tumor microfluidic ecology. Proceedings of the National Academy of Sciences, 113(50), 14283-14288.