Physical Dynamics of Cancer Response to Chemotherapy in 3D Microenvironments
List of Collaborating Institutions
Vanderbilt University, Tennessee
H. Lee Moffitt Cancer Center & Research Institute
Our project aims to develop a new computationally driven platform to examine complex physical and chemical microenvironments utilizing organ-on-chip microfluidic bioreactor technology coupled with a predictive mathematical model of tumor growth and therapeutic response. Malignant breast tumors are highly heterogeneous in terms of their cellular composition, varying levels of oxygenation, acidity, and nutrients, as well as local changes in the extracellular matrix. Furthermore, tumor tissue and tumor microenvironment properties can dynamically evolve not only during tumor growth but also when anticancer treatments are administered. Despite this, nearly all pre-clinical assessments of drug efficacy and optimal dosing are performed using homogeneous 2D cell cultures that do not resemble the cellular, metabolic, and physical features manifest in tumors in vivo. Such approach suffered from overly reductionist ex vivo/in vitro and studies may not fully recapitulate the complexity of cancers, especially their physical and chemical microenvironments. To address these issues, we concentrate on developing an integrated quantitative platform that combines the power of organ-on-chip 3D tissue bioreactor, developed to include non-uniform fully controlled physical and chemical microenvironments, together with a 3DMultiCell math model that allows predictive testing of a broad range of microenvironmental combinations around the experimentally validated baseline.
- Develop a predictive methodology to assess effects of defined microenvironments on the dynamics of normal and tumorigenic breast organoids and their sensitivity to therapeutics.
- Construct and validate in silico model-guided complex spatial and temporal microenvironmental gradients established within TTb-G reactor, and assess breast tumor organoids response to chemotherapeutics
- Apply our integrated computational/engineering approach to guide therapy and predict therapeutic response ex vivo and in vivo
Mammary on chip bioreactor for studying complex physical and chemical microenvironments in breast cancer coupled with a predictive mathematical model of tumor growth and therapeutic response. A) Thick Tissue bioreactor diagram. B) Selected confocal slices of the mammospheres produced by MCF cell variants cultured within TTB for 21 days. C) Mammosphere formation after proteinase inhibitor treatments. D) Inhibition of proteinase activity. (A-D: Taken from Markov et al, Lab Chip, 21:4560-8, 2012). E) An example of the growth of 3D in silico spheroids (grey) under the heterogeneous microenvironmental gradient (high concentration in red, low concentration in blue).
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Lisa J. McCawley, Ph.D.
Dr. McCawley is a Research Associate Professor in the Departments of Biomedical Engineering and Cancer Biology at Vanderbilt University, Nashville TN and a faculty fellow of the Vanderbilt Institute for Integrative Biosystems Research and Education (VIIBRE). Dr. McCawley received her Ph.D. in 1998 with an emphasis in Pharmacology/Toxicology from Northwestern University, Chicago IL. Her background is in the area of matrix metalloproteinases (MMPs) and how they regulate cellular processes that contribute to tissue remodeling processes. Current research is directed towards understanding how changes in cell populations and other factors of the tissue microenvironment (ie., oxygenation state, pH and matrix composition) influence wound repair and tumor progression. With her engineering collaborations in VIIBRE, she is developing and applying BioMEMS to interrogate the biophysical and biochemical processes governing cellular migration, transendothelial migration and tissue invasion. She is developing bioreactors to reconstitute tissue using cellular populations (i.e., immune cells, endothelial cells, fibroblasts, normal and/or tumorigenic epithelial/epidermal cells) and/or maintain tissue biopsies under normal (physiological) and/or diseased (pathological) conditions. She is continuing the development of Organ-on-a-Chip style microfluidic bioreactors targeting three-dimensional cell cultures in the areas of mammary development and response to environmental toxins; breast tumorigenesis and response to therapy in complex microenvironments; and the blood brain barrier.
Dmitry A. Markov, Ph.D.
Dr. Dmitry A Markov is a Research Assistant Professor in the Department of Biomedical Engineering at Vanderbilt University and a faculty fellow of Vanderbilt Institute for Integrative Biosystems Research and Education (VIIBRE), Nashville, TN. He received his Ph.D. in Electrical Engineering at Texas Tech University in 2004 developing optical methods for refractive index measurements in nanoliter volumes and employing laser interferometry to study label-free protein – surface and protein – protein interactions. Dr. Markov’s multidisciplinary research interests lay at the intersection of biological sciences and engineering. In particular, he focuses on the development of instrumented Microphysiological Systems for breast cancer research that reconstitute non-pathological and diseased-tissue specific microenvironments ex vivo utilizing cell populations or intact tissue biopsies. These Organ-on-a-Chip style microfluidic bioreactors allow for studying disease progression, treatment options, testing effects of environmental pollutants on mammary tissue development, and perturbations of the blood-brain barrier.
Katarzyna A. Rejniak, Ph.D.
Katarzyna A. Rejniak (“Kasia”), Ph.D. is a founder member of the Integrated Mathematical Oncology Department at the Moffitt Cancer Center. She joined Moffitt faculty in 2008 after completing two postdoctoral fellowships, first at the NSF-funded Mathematical Biosciences Institute at the Ohio State University; and second as a joint postdoc at the Dundee University in Scotland and the Vanderbilt Integrative Cancer Biology Center in Nashville. She received MSc degree in mathematics and computer science from Gdansk University in Poland, and Ph.D. in applied mathematics from Tulane University in New Orleans, Louisiana, in 2002. Kasia specializes in mathematical modeling of complex interactions between tumor cells and tumor microenvironment, especially she is investigating how the heterogeneous microenvironments influence tumor response to anticancer treatments, and how tumor stroma and tumor tissue is penetrated by drug molecules, imaging agents and various metabolites.
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