(175k) Dynamics of Circulating Tumor Cells inside Microfluidic Separators

Circulating tumor cells (CTCs) are cancer cells that leave their site of origin and spread throughout the body to form new cancer sites. CTCs are the base of metastasis - the uncontrolled formation of new, distant tumors originating from the primary tumor. Metastasis is associated with poor recovery prognosis, prompting research on CTC characteristics, detection, and breakdown [1].

CTCs were shown to display a range of complex interactions such as intercellular communication [2-3], leader-follower relationships [2], and grouping into aggregates [2, 4]. These unordinary characteristics make CTCs more mobile and resilient to immune response and mechanical damage in the bloodstream [2, 4].

Early detection of CTCs in the bloodstream of cancer patients is thought to improve their chances of recovery [4]. Moreover, as cancer therapy evolves, the isolation of patient-specific CTCs may lead to improved, personalized treatment. Finally, capturing and cultivating these cells enables further research. Microfluidic separators are a class of microtechnology-based devices that show promise in accomplishing efficient isolation of CTCs from cell mixtures, including bloodstream components [4-6]. One particularly promising class of separators relies exclusively on cleverly tuned hydrodynamics in the device to achieve the desired partitioning. By manipulating the flow of fluids through innovative design solutions, researchers can separate different cells based on their deformability, sizes, and shapes [4-6]. The flow of these cells is characterized by rich physics that involves their interaction with the device features, the surrounding fluid, and themselves [4-6].

Recently, our group developed a simple mathematical model of cellular interactions and applied it to simulate tumor cells [7]. Our model successfully reproduced experimental results on a variety of interactions and clustering propensities of breast cancer cells. Using it, we were able to evaluate the capabilities of a newly proposed CTC cluster detection assay beyond its original, simplified operating conditions. In this work, we leverage our model to characterize the dynamics of CTCs and their clusters in an external, microfluidic flow. In particular, we study the behavior of cells and their aggregation inside a straight microfluidic channel as well as a simple microfluidic separator. Due to the simplicity and modularity of our model, we can draw unique conclusions about the interaction between cells, cells and device walls, their clustering tendencies, and their response to the flow.

[1] Massague, J. and Ganesh, K., 2021. Metastasis-initiating cells and ecosystems. Cancer Discovery, 11(4), pp.971-994.

[2] Wrenn, E., Huang, Y. and Cheung, K., 2021. Collective metastasis: coordinating the multicellular voyage. Clinical & Experimental Metastasis, 38, pp.373-399.

[3] Jiang, Y., Liu, X., Ye, J., Ma, Y., Mao, J., Feng, D. and Wang, X., 2023. Migrasomes, a new mode of intercellular communication. Cell Communication and Signaling, 21(1), p.105.

[4] Schuster, E., Taftaf, R., Reduzzi, C., Albert, M.K., Romero-Calvo, I. and Liu, H., 2021. Better together: circulating tumor cell clustering in metastatic cancer. Trends in Cancer, 7(11), pp.1020-1032.

[5] Tang, H., Niu, J., Jin, H., Lin, S. and Cui, D., 2022. Geometric structure design of passive label-free microfluidic systems for biological micro-object separation. Microsystems & Nanoengineering, 8(1), p.62.

[6] Amini, H., Lee, W. and Di Carlo, D., 2014. Inertial microfluidic physics. Lab on a Chip, 14(15), pp.2739-2761.

[7] Kirchner, Z., Geohagan, A. and Truszkowska, A., 2024. A Vicsek-type model of confined cancer cells with variable clustering affinities. Integrative Biology, 16, p.zyae005.