Interaction of Circulating Tumor Cells with Platelets: from Physiology to Diagnostics

Though known for their primary role in maintaining hemostasis, thrombosis, and promoting wound healing, platelets have been implicated in supporting circulating tumor cell (CTC) dissemination and promoting metastatic development. Metastasis refers to the process by which tumor cells break away from the primary tumor, enter the bloodstream, and eventually extravasate the bloodstream into distant tissues. Platelets not only modulate primary tumor growth, but they also play a determinant role in the metastatic cascade. Upon entering the bloodstream, platelets immediately interact with CTCs and bind to their surface, subsequently protecting CTCs from shear stress in the bloodstream, promoting immune evasion, and promoting CTC arrest within the vasculature. Several studies have shown that platelet depletion indeed leads to significant decreased in metastases. Platelet-cancer cell interactions can be mediated via direct receptor-receptor binding present on their surfaces or with receptor bridging via adhesion proteins. There has been a variety of interactions between platelets and cancer cells that have been characterized in literature, thus providing many opportunities for potential new diagnostic and therapeutic targets.The scope of work described in this dissertation seeks to leverage naturally occurring platelet-cancer cell interactions to develop a diagnostic tool for metastasis and potentially identify therapeutic targets. We first seek to gain further understanding of platelet-cancer cell interactions and how physiology and the microenvironment can module platelet-cancer cell interactions. Specifically, we assessed how calcium levels can affect the interactions between platelets and cancer cells via integrins and influence cancer cell invasion. Because calcium is important for the stability of specific integrins implicated in platelet-cancer cell interactions, a greater understanding of such interactions could lead to potentially new therapeutic targets. CTCs are indeed an essential biomarker for metastatic disease because they provide valuable information regarding the primary tumor, metastatic potential and potentially prognosis, as well as patient monitoring. They could also aid in guiding personalized therapy for a patient. However, successful detection, isolation, and enumeration of CTCs remains a challenge due to their infrequency in patient biopsy samples, heterogeneity, and dynamic properties. Therefore, we designed a non-antibody-based system that leverages platelet-cancer cell interactions to target and retrieve CTCs from a liquid biopsy sample by engineering magnetic platelet decoys. We hypothesized that the magnetic platelet decoys will theoretically be applicable for the capture and retrieval of all CTCs, regardless of origin or phenotype. Metastatic in vivo models are pertinent tools mimicking the myriad of complex events that occur in the metastatic process. Thus, we seek to apply the magnetic platelet decoys developed for retrieval from cancer patient sample to retrieving CTCs from an experimental metastatic in vivo model. We present a pilot study that demonstrates the potential of using the system to capture CTCs from an in vivo model for the numeration and further characterization. Future work will aim to develop the magnetic platelet decoys into a complementary method for assessing and characterizing metastatic burden.

Author

• Morris, Kenise

Language

• English

Date created

• 2024

Type of Work

• Dissertation

License

• All rights reserved

Rights statement

• In Copyright

GW Unit

• Biomedical Engineering

Degree

• D.Sc.

Advisor

• Papa, Anne-Laure

Committee Member(s)

• Entcheva, Emilia
• Fernandes, Rohan
• Li, Zhenyu
• Kay, Matthew

Persistent URL

•  https://scholarspace.library.gwu.edu/etd/rn301228n