Metastatic disease is resistant to current therapies and remains the primary cause of cancer-related death. Exploring the earliest events that promote circulating tumor cells (CTCs) to arrest on vessel wall at future metastatic sites will expose new targets for rational prevention. In addition to biological factors, the physical transport of CTCs and interactions with the microenvironment are regarded as key determinants of the metastatic potential. Recent studies suggest that distant microenvironments are primed and ready to entrap CTCs, creating a pre-metastatic niche for initiating metastasis. Our preliminary data shows a time- and organ-dependent increase in platelet (PLT) accumulation and activation in vessels of both lung and liver in mice bearing primary breast cancer, prior to spontaneous metastasis to these organs. We also found blood flow velocity was heterogeneously reduced in capillaries of the liver before development of metastasis, indicating changes in flow dynamics in vessels of the future metastatic sites may be involved in the process of initiating metastasis. Whereas direct biological effects of PLT on cancer cells are well known, the roles of PLT in the development of the pre-metastatic niche and the effects of these PLTs on biophysical transport mechanisms of CTCs have not been reported. Our objective is to determine biophysical modulation of CTC transport by the pre-metastatic niche initiated by PLTs using orthotropic mouse tumor models, novel microfluidics, and multiscale/multi-physics computational transport models. Our hypotheses are: 1) there is an organ- and time-dependent development/evolution of the pre-metastatic niche alters hydrodynamics for CTCs; 2) only the pre-metastatic niche, which is sufficiently developed to alter these biophysical parameters, promotes arrest of CTCs on vessel walls; and 3) modulation of PLT functionality by anti-PLT reagents affects biophysical roles of PLTs in the pre- metastatic niche on CTC transport and the prospect of metastasis. The multiscale/multi-physics transport approach will optimize parameterization of cancer metastasis based on experimental results in vivo and in vitro, in order to characterize biophysical transport mechanisms of CTCs interacting with pre-metastatic niche. Significance of this study will establish a scientific framework for understanding roles of the pre-metastatic niche evolution initiated with PLTs in physical oncology for rational prevention of metastasis. Innovation of our proposal is to elucidate unknown biophysical roles of the pre-metastatic niche on CTCs transport and to employ computational oncophysical transport model incorporating multi-scale and multi-physics capabilities. To test our hypothesis, we propose the following Specific Aims (SA): SA1: To understand the flow fundamentals in vessels as a function of development/evolution of the pre-metastatic niche. SA2: To evaluate the biophysical effect of accumulated and activated PLTs in the pre-metastatic niche on CTC transport in vessels. SA3: To determine the effect of biophysical modulation of PLT functions on CTCs transport using anti-PLT reagents.

Metastatic disease is resistant to current therapies and remains the primary cause of cancer related death. We identified that specific distant organs away from the primary tumor can create the “pre-metastatic niches” for future metastasis initiation by recruiting platelets to vessel wall which will in turn support circulating tumor cell to slowdown and attach on the vessel wall, thus affecting physical transport of cancer cells. Objective of this proposal is to elucidate the both biological and physical roles of the pre-metastatic niche for initiation of metastasis and we anticipate that the proposed research will bring a strong scientific framework for elucidate unknown role of platelets for initiating metastasis and rational prevention of metastasis.