2013 Otto Schmitt Lecture (Toner) | Institute for Engineering in Medicine Archives

"Rare Events with Large-Impact: Bioengineering & Clinical Applications of Circulating Tumor Cells"

11:30 AM - 12:30 PM
Tuesday, December 3, 2013

ABSTRACT

Viable tumor-derived circulating tumor cells (CTCs) have been identified in peripheral blood from cancer patients and are probably the origin of intractable metastatic disease. However, the ability to isolate CTCs has proven to be difficult due to the exceedingly low frequency of CTCs in circulation. We introduced several microfluidic methods to improve the sensitivity of rare event CTC isolation, a strategy that is particularly attractive because it can lead to efficient purification of viable CTCs from unprocessed whole blood.

The micropost CTC-Chip (μpCTC-Chip) relies on laminar flow of blood cells through anti-EpCAM antibody-coated microposts, whereas the herringbone CTC-Chip (HbCTC-Chip) uses micro-vortices generated by herringbone-shaped grooves to efficiently direct cells toward antibody-coated surfaces. These antigen-dependent CTC isolation approaches led to the development of a third technology, which is tumor marker free (or antigen-independent) sorting of CTCs. We call this integrated microfluidic system the CTC-iChip, based on the inertial focusing strategy, which allows positioning of cells in a near-single file line, such that they can be precisely deflected using minimal magnetic force. We applied these three microfluidic platforms to blood samples obtained from lung, prostate, breast, colon, melanoma, and pancreatic cancer patients. We isolated CTCs from patients with metastatic non-small-cell-lung cancer and identified the EGFR activating mutation in CTCs. We also detected the T790M mutation, which confers drug resistance. We also applied microchip to isolate CTCs from blood specimens of patients with either metastatic or localized prostate cancer, and showed the presence of CTCs in early disease.

Remarkably, the low shear design of the HBCTC-chip revealed micro-clusters of CTCs in a subset of patient samples. Microscopic CTC aggregates may contribute to the hematogenous dissemination of cancer. More recently, we used microfluidic capture of CTCs to measure androgen receptor (AR) signaling readouts before and after therapeutic interventions using single-cell immunofluorescence analysis of CTCs. The results support the relevance of CTCs as dynamic tumor-derived biomarkers, reflecting “real time” effects of cancer drugs on their therapeutic targets, and the potential of CTC signaling analysis to identify the early emergence of resistance to therapy. We also characterized epithelial-to-mesenchymal transition (EMT) in CTCs from breast cancer patients. While a few primary tumor cells simultaneously expressed mesenchymal and epithelial markers, mesenchymal cells were highly enriched in CTCs, and most importantly, serial CTC monitoring suggested an association of mesenchymal CTCs with disease progression suggesting a role for EMT in the blood-borne dissemination of human breast cancer.

This presentation will share our integrated strategy to simultaneously advance the engineering and microfluidics of CTC-Chip development, the biology of these rare cells, and the potential clinical applications of circulating tumor cells.

BIOGRAPHY

Mehmet Toner is a professor of surgery (Biomedical Engineering) at the Massachusetts General Hospital, Harvard Medical School, and is the founding director of the NIH BioMEMS Resource Center.

Dr. Toner was born in Istanbul, Turkey in July 1958. Dr. Toner received a Bachelor of Science degree from Istanbul Technical University in 1983 and an M.S. degree from the Massachusetts Institute of Technology (MIT) in 1985, both in Mechanical Engineering. He subsequently completed his Ph.D. in Medical Engineering at the Harvard-MIT Division of Health Sciences and Technology (HST) in 1989. He joined the faculty at the Massachusetts General Hospital (MGH) and Harvard Medical School as an Assistant Professor of Biomedical Engineering in 1989, and was promoted to Associate Professor in 1996, and to Professor in 2002. Dr. Toner has a joint appointment as a Professor of Health Sciences and Technology at the Harvard-MIT Division of HST.

Dr. Toner serves as a member of the Senior Scientific Staff at the Shriners Hospital for Children. He is a co-founder of the Center for Engineering in Medicine, and founder of the NIH BioMicroElectroMechanical Systems (BioMEMS) Resource Center at the MGH. He is also the Director of the Biomedical Engineering Research and Education Program for physicians at MGH. Dr Toner is a member of many national and international professional committees, and serves on the editorial board of many scientific journals including Cryobiology, Cryo-Letters, Cell Preservation Technology, Annual Reviews in Biomedical Engineering, and Nanomedicine. He has served on many national and international panels and review boards, including National Institutes of Health (NIH) Study Sections, National Science Foundation (NSF) CAREER Award panels, NSF Nanoscience panel, NIH Nanotechnology and Tissue Engineering panel, and several DARPA strategic planning panels.

In 1994, he was recognized by the YC Fung Faculty Award in Bioengineering from the American Society of Mechanical Engineers (ASME). In 1995, he received the Whitaker Foundation Special Opportunity Award. In 1997, he won the John F and Virginia B Taplin Faculty Fellow Award given by Harvard and MIT. In 1998, Dr. Toner was selected to become a Fellow of the American Institute of Medical and Biological Engineering. Dr. Toner serves on the Scientific Advisory Board of multiple biotechnology and medical device companies, and has been involved as a scientific founder of multiple startup companies.

Dr. Toner is internationally recognized for his multidisciplinary approach to biomedical problems in the areas of low-temperature biology and biostabilization, tissue engineering and artificial organs, and microsystems bioengineering in clinical medicine and biology. Dr Toner has received funding from NIH, NSF, DARPA, Whitaker Foundation, National Textile Center, and many industrial outfits. Dr. Toner’s former students and trainees hold positions at many prestigious universities and companies, including MIT, Harvard, UCSD, UC Irvine, UC Davis, Rutgers U, University of Minnesota, Georgia Institute of Technology, University of Amsterdam, Keio University, University of Alberta, Amgen, Bristol-Myers, and BioLife. He has published over 300 scientific publications and has delivered over 400 invited and scientific meeting presentations.