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Mehmet Toner

Mehmet Toner - Harvard Medical School/MGH

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

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 (?pCTC-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: Dr. Toner received his bachelor's degree in mechanical engineering from Istanbul Technical University in 1982; and his master's degree, also in mechanical engineering, from the Massachusetts Institute of Technology (MIT), Cambridge, in 1985. He earned his Ph.D. in medical engineering at Harvard-MIT Division of Health Sciences and Technology in 1989. Currently he is the Helen Andrus Benedict professor of biomedical engineering at the Massachusetts General Hospital (MGH), Harvard Medical School in Boston.

Toner is internationally regarded for his work in multiple areas at the interface of bioengineering and life sciences including micro/nanotechnology and applications in cancer. He established the Bio MicroElectroMechanical Systems Resource Center (BMRC) at MGH and serves as its founding director. Primarily funded by the National Institutes of Health (NIH), BMRC aims to explore the applications of nano/micro-technologies in basic biology, systems biology, diagnostics and clinical medicine.

Among the more than 70 graduate and postgraduate students trained by Toner, more than 40 occupy major academic positions. Many of his alumni have received the National Science Foundation (NSF) CAREER Award, NSF Presidential Young Investigator Award, NIH FIRST Award and NIH Director's Young Investigator Award; and many have been elected a Fellow of the American Institute for Medical and Biological Engineering and/or ASME. A number of his former students secured endowed chairs or other prestigious awards such as Howard Hughes Medical Institute Investigator.

Toner has served on many national and international panels and review boards. In 2010 he was selected to serve a three-year term on the NSF Directorate for Engineering's Advisory Committee. He is a trustee of the Özye?in University in Istanbul and a member of the President's Council at the Franklin W. Olin College of Engineering. He serves on the scientific advisory board of the Tissue Engineering Resource Center at Tufts University/MIT/Columbia University, the Resource for Synthesis and Bulk Characterization of Polymer Biomaterials at Rutgers University, the Institute for Engineering in Medicine at the University of Minnesota, the Center for Biomedical Engineering and Science at the University of North Carolina at Charlotte and the Center for Biomedical Engineering and Science at Brown University.

He is also on the editorial board of various technical and scientific journals including CryoLetters, Cryobiology (associate editor), Cell Preservation Technology (associate editor), Nanomedicine, Integrative Biology, Nanolife and the Annual Review of Biomedical Engineering (associate editor and co-founder).

Toner has published more than 250 original papers in archival journals including a wide spectrum of high impact journals such as Nature, Science, the New England Journal of Medicine, Science Translational Medicine, Nature Biotechnology and PNAS (Proceedings of the National Academy of Sciences). He has also delivered more than 350 invited, keynote and plenary presentations.

An ASME Fellow, Toner has been a member of the Bioengineering Division's (BED) Biotransport Technical Committee (formerly K-17 Heat and Mass Transfer in Biotechnology Committee) since 1992. He was the associate technical editor of the Journal of Biomechanical Engineering (1998-2004) and now serves on the editorial board. Toner was honored with BED's Y.C. Fung Investigator Award in 1994.

He is also a Fellow of the American Institute for Medical and Biological Engineering and the International Society of Cryobiology.

Among his other honors, Toner received the Whitaker Foundation Special Opportunity Award (1995) and MGH Cancer Center's "One-of-the-hundred" award (2008), was recognized by Popular Mechanics as one of the top ten inventors (2008) and received the American Association for Cancer Research's Team Science Award (2010).

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