Houston Methodist Research Institute PS-OP

Biophysical roles of pre-metastatic niche evolution on transport of circulating tumor cells

Exploring the earliest events that promote circulating tumor cells (CTCs) to immobilize on blood vessel walls at future metastatic sites will expose new targets for rational prevention. Studies suggest that distant microenvironments are primed and ready to entrap CTCs, creating a pre-metastatic niche for initiating metastasis. In addition to biological mechanisms, the physical transport of CTC in blood vessels and biophysical interaction of CTC with the pre-metastatic niche can be regarded as key determinants of metastatic potential.

Although the biological effects of circulating platelets on CTCs and platelets accumulating to primary and metastatic tumors to support tumor growth and invasion are known, the roles of platelets in the initiation and development of the pre-metastatic niche and biophysical effects of the PLT on transport of CTCs in blood vessels have not been reported.

This PS-OP is elucidating and validating the biophysical roles of the pre-metastatic niche initiated with platelets in the future metastatic site on CTC transport.

PS-OP investigators integrate orthotopic mouse tumor models using cell lines with different metastatic potentials, novel microfluidics pre-coated with or without platelets, and multiscale/multi-physics computational transport models.

The hypotheses of the PS-OP include:

• There is an organ- and time-dependent initiation/evolution of the pre-metastatic niche, wherein deposited and activated platelets on vessel walls in mice bearing primary tumors alters hydrodynamics of CTCs and their interactions.
• Only the pre-metastatic niche, which is sufficiently developed to significantly alter these biophysical parameters, promotes immobilization of CTCs on vessel walls
• Modulation of platelet functionality by anti-platelet reagents affects biophysical roles of platelets on CTC transport and the prospect of metastasis.

Multiscale/multi-physics transport modeling provides optimized parameterization of metastasis based on experimental results in vitro and in vivo to characterize transport phenomena of CTCs and phenotype pre-metastatic niches.

The significance of this study will establish a scientific framework for understanding undiscovered biophysical roles of the pre-metastatic niche initiated with platelets on transport of CTCs for rational prevention of metastasis using anti-platelet reagents.

Investigators

Kenji Yokoi, M.D., Ph.D.
Houston Methodist Research Institute

Dr. Kenji Yokoi is a Faculty and an Assistant Professor in Nanomedicine, Institute for Academic Medicine, Assistant Member, Houston Methodist Research Institute. He has a background in surgical oncology and cancer biology. His expertise includes the establishment and therapy of various primary and metastatic mouse tumor models, as well as biological, molecular biological, and proteomic analysis of tumor specimen and cancer cell lines.

He has extensive experiences in histological, immunohistochemical and immunofluorescence analysis of tumor sections. Since moving to the Department of Nanomedicine at the Houston Methodist Research Institute from the Department of Cancer Biology, MD Anderson Cancer Center, he has focused research on tumor microenvironments and its roles on the transport of various mass and therapeutics using orthotopic mouse tumor models. For these purposes, he has utilized several imaging techniques including confocal microscopy, and Intravital microscopy.

Lidong Qin, Ph.D.
Houston Methodist Research Institute

Dr. Lidong Qin is a Professor at the Houston Methodist Research Institute, and he directs the Methodist Hospital Biomicrofluidics laboratory. He has more than ten years of experience in microfluidics and nanotechnology research, which include high throughput cell deformability analysis by using microfluidic chips. Dr. Qin has developed innovative biotechnological tools with the use of polydimethylsiloxane (PDMS), glass, plastic, and silicon-based nanoelectronic/microfluidic devices.

His research sponsors include NIH/NCI, NIDA, NIA, Alliance of Nanohealth, Cancer Prevention and Research Institute of Texas (CPRIT), Emily Herman Research Foundation, Golfers Against Cancer Foundation, and others. Dr. Qin’s research team has demonstrated leadership in the field of microfluidics biotechnology and his research has been featured in journals including Nature Communications, Proceedings of the National Academy of Sciences, Science Advances, Journal of the American Chemical Society, Angewandte Chemie, Trends in Biotechnology, and others.

Milos Kojic, Ph.D.
Houston Methodist Research Institute

Dr. Milos Kojic is a professor and senior member at the Department of Nanomedicine, Houston Methodist Research Institute. He is the worldwide leading authority in Finite Element modeling with more than 30 years of research which spans form nonlinear analysis in solid mechanics and field problems to various topics in bioengineering and multiscale models. His previous positions include University of Kragujevac, Serbia (professor of Mech. Eng.), MIT (visiting scholar), ADINA R&D Software Company Boston (research engineer), Harvard University (senior research scientist), University of Texas Medical Center at Houston (research professor).

Currently, Dr. Kojic works actively in development of multiscale model for biomedical and bioengineering applications, and focusing on drug/mass transport problems. His main scientific focus will be further developing and advancing novel multiscale and Finite Element models for the prediction of drug/mass transport in tumor microenvironment.