Metastasis and Biophysics of Clusters of Circulating Tumor Cells in the Microcirculation
List of Collaborating Institutions
Massachusetts General Hospital
Harvard Medical School
Circulating tumor cells drive metastasis when they travel from primary tumors to distant organs via the circulation. Multicellular clusters of circulating tumor cells though less frequently observed in blood, are much more likely to establish metastases than individual circulating tumor cells and the presence of tumor clusters in blood has been associated with dramatically worse prognoses in patients. Although there are many suspected explanations for their greater metastatic potentials, much is still unknown about the behavior of clusters, especially in the narrow vessels of the body. Recent evidence has demonstrated that cluster transiting through narrow constrictions experience dynamic changes to structure and organization. Forces in the microcirculation cause clusters to reversibly re-organize into single-file chains to enable transit through narrow capillary-sized vessels and nuclear envelopes are ruptured and rapidly repaired during migration events through narrow constrictions. Two biophysical parameters within clusters, cellular adhesion strengths and nuclear mechanics, are vital for these behaviors. Because of the important role that these parameters play in many aspects of metastatic progression, we hypothesize that these parameters modulate the biophysical responses of clusters to physical forces in the microcirculation, and that these interactions play a significant role in the competitive edge that clusters have edge over individual cancer cells for seeding metastases. To this end, we propose three specific aims. In aim 1, we will develop next generation models of the human microcirculation with rounded networks of endothelial cell coated microfluidic devices and geometry matched computational simulations. In aim 2, we will explore how intercellular adhesions affect the biophysical responses and metastasis-forming abilities of homogeneous versus heterogeneous clusters in the microcirculation through the use of our developed models. Finally, in aim 3 we will study the physical basis for nuclear envelope rupture, DNA-damage, genetic instability and other DNA-level affects that are involved in metastatic progression. Understanding the interplay between the biophysics and biology of clusters within the microcirculation will elucidate mechanisms that can be used to combat the progression of cluster-initiated metastases.
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Mehmet Toner, PhD
Dr. Toner is the Helen Andrus Benedict Professor of Biomedical Engineering at the Massachusetts General Hospital, Harvard Medical School, and Harvard-MIT Division of Health Sciences and Technology. He has been on the Scientific Staff of the Shriners Hospital for Children in Boston since 1990. Dr. Toner co-established the Center for Engineering in Medicine, and BioMicroElectroMechanical Systems Resource Center (BMRC) at the MGH to explore the applications of bioengineering in basic biology, systems biology, diagnostics and clinical medicine. He is the Director of Research at the Shriners Hospital for Children Boston. His research interests include microfluidics, micro- and nano-technology, low temperature biology, and tissue engineering. His interest in microfluidics has focused on the use of single particle precision of microfluidics for large volumes and complex bodily fluids such as blood. He has developed a microfluidic sorter to isolate circulating tumor cells and clusters from the blood of cancer patients together with Drs. Haber and Maheswaran.
Daniel A. Haber, MD, PhD
Dr. Haber is Director of the Massachusetts General Hospital Cancer Center and the Kurt J. Isselbacher Professor of Oncology at Harvard Medical School. His laboratory interests have focused on the area of cancer genetics, including the etiology of the pediatric kidney cancer Wilms tumor, genetic predisposition to breast cancer, and targeted cancer therapies. His laboratory reported that lung cancers with activating mutations in the epidermal growth factor receptor (EGFR) are uniquely sensitive to tyrosine kinase inhibitors that target this receptor. This observation has had important implications for the genotype-directed treatment of non-small cell lung cancer, and more broadly for strategies to identify critical genetic lesions in cancers that may serve as an "Achilles heel" and be suitable for molecular targeting. In collaboration with Dr. Mehmet Toner’s laboratory, Dr. Haber’s laboratory has recently established the application of a novel microfluidic technology for quantifying and purifying Circulating Tumor Cells (CTCs) from the blood of patients with various epithelial cancers. This new application has potentially profound implications for early diagnosis of cancer and for noninvasive molecular profiling of cancers during the course of therapy.
Shyamala Maheswaran, PhD
Dr. Maheswaran is an Associate Professor in Surgery at Harvard Medical School and the Co-Director of the Circulating Tumor Cell Laboratory at the Massachusetts General Hospital Cancer Center. She is an authority in breast cancer biology and in molecular biology. Her long-term interest in the field of cancer biology has led to her leadership of collaborations with physicians, scientists and engineers, focused on the molecular applications of the CTC-iChip technology. Dr. Maheswaran graduated from the University of Peradeniya in Sri Lanka and received her doctorate in Biochemistry and Molecular Biology from Boston University, MA. Her research includes several high-profile publications ranked in the top 1% of the academic field of Molecular Biology and Genetics based on a highly cited threshold for the field and publication year.
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