Research Papers

The Mechanics of Single Cell and Collective Migration of Tumor Cells

[+] Author and Article Information
Marianne Lintz, Adam Muñoz

The Nancy E. and Peter C. Meinig
School of Biomedical Engineering,
Cornell University,
309 Weill Hall,
Ithaca, NY 14853

Cynthia A. Reinhart-King

The Nancy E. and Peter C. Meinig
School of Biomedical Engineering,
Cornell University,
302 Weill Hall,
Ithaca, NY 14853
e-mail: cak57@cornell.edu

1Contributed equally to this work.

2Corresponding author.

Manuscript received July 4, 2016; final manuscript received October 28, 2016; published online January 19, 2017. Assoc. Editor: Victor H. Barocas.

J Biomech Eng 139(2), 021005 (Jan 19, 2017) (9 pages) Paper No: BIO-16-1281; doi: 10.1115/1.4035121 History: Received July 04, 2016; Revised October 28, 2016

Metastasis is a dynamic process in which cancer cells navigate the tumor microenvironment, largely guided by external chemical and mechanical cues. Our current understanding of metastatic cell migration has relied primarily on studies of single cell migration, most of which have been performed using two-dimensional (2D) cell culture techniques and, more recently, using three-dimensional (3D) scaffolds. However, the current paradigm focused on single cell movements is shifting toward the idea that collective migration is likely one of the primary modes of migration during metastasis of many solid tumors. Not surprisingly, the mechanics of collective migration differ significantly from single cell movements. As such, techniques must be developed that enable in-depth analysis of collective migration, and those for examining single cell migration should be adopted and modified to study collective migration to allow for accurate comparison of the two. In this review, we will describe engineering approaches for studying metastatic migration, both single cell and collective, and how these approaches have yielded significant insight into the mechanics governing each process.

Copyright © 2017 by ASME
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Grahic Jump Location
Fig. 1

Cartoon depiction of the metastatic process. (a) To metastasize, cells in the (1) primary tumor, located at position 1; (2) separate and undergo EMT; (3) invading through local tissues surrounding the initial lesion before (4) intravasating from the basement membrane into the vasculature or lymphatic system. Metastatic cells then begin to travel as CTCs or CTM through the vasculature. (b) Cells in the metastatic cluster (5) adhere to the basement membrane and then (6) exit at a distal location in a process called extravasation to (7) form a tumor at a secondary site. Arrows indicate direction of migration.

Grahic Jump Location
Fig. 2

Mechanisms of cell migration. Modes of single cell migration include (a) amoeboid, characterized by blebbing, weak adhesions, and rapid polarity and (b) mesenchymal, characterized by strong stress fibers, polarization, and the presence of a leading and trailing edge. (c) Collective migration consists of a connected unit of cells, fronted by a select few leader cells (indicated by darker cells to the far right).

Grahic Jump Location
Fig. 3

Cartoon representation of single and collective migration assays. (a) Matrix models for studying single cell migration, where cells are either seeded on 2D substrates (bottom) or embedded within 3D substrates (top). (b) Microfluidic model for studying single cell migration. Generally, the horizontal center channel is seeded with metastatically invasive cells in an ECM matrix and the outer horizontal channels are filled with varying types of media or chemogradients. While the vertical channels are used to study the migration characteristics of the cells. (c) Microtrack model for studying single cell migration. (d) Spheroid (left) and organoid (right) models for studying collective migration. Indicated by darker cells in the organoid model represent the heterogeneity of the cells taken from sources such as patient samples, mice, xenografts.




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