Cancer cells evade confinement


The ability of epithelial cells to move is like a double-edged sword.  At the interface between the body and the external world, humans need epithelial cells to constantly move and reposition in order to maintain the integrity of epithelial layers, compensate for dying cells or wounds, and protect against bacteria and other microbes.  However, when epithelial cells become malignant, they leave the tumors and set in motion a chain of events that ends with the death of the patient.  Metastases are ultimately responsible for more than 90% of cancer-related deaths.  To understand how to control the migration of cancer cells, investigators need new tools for measuring cell motility in relevant conditions. Read More

The great escape:  cancer cells find their way through mazes

Cancer cell migration is commonly assumed to be directed by pre-existent spatial gradients of chemokines and growth factors in the target tissues. Unexpectedly however, MGH investigators found that the guided migration of epithelial cells is possible in vitro in the absence of pre-existent chemical gradients. We observed that both normal and cancer epithelial cells can migrate persistently and reach the exit along the shortest path from microscopic mazes filled with uniform concentrations of media. ► View the maze solving abilities of cancer cells. Using microscale engineering techniques and biophysical models, the investigators uncovered that the self-guidance strategy depends on the uptake of epidermal growth factor (EGF) by the epithelial cells, and the formation of EGF gradients in conditions of biochemical and mechanical confinement.  Better understanding of the processes involved in the self-guidance strategy could eventually help devise new ways for modulating epithelial cell migration and delaying cancer cell invasion or accelerating wound healing

EMT accelerates cancer cell invasion

During cancer progression, the transformation of adherent cells to a motile phenotype (also known as epithelial–mesenchymal transition (EMT), increases their ability to invade into surrounding and distant tissue.  One critical feature of invasive cells is their ability to break away from their neighbors and migrate alone or in small clusters.  Using new microfluidic designs with micropillar arrays, investigators can now monitor the precise time when EMT-activated cells transition from a collectively advancing front to scattered individual cells. ► View the collective and individual migration of an induced EMT population. Control experiments show the collective migration of epithelial cells (► view). Using this technology, individual cells with few neighbors disperse with fast, straight trajectories, whereas cells with many neighbors migrated collectively with epithelial biomarkers.  A surprising degree of phenotypic plasticity can also be quantified, as cells interconvert between individual and collective migration.  The study of multicellular behaviors with single-cell resolution should enable further quantitative insights into heterogeneous tumor invasion.

At 200 microns per hour, cancer cells can invade more than 4 inches in one month

When cancer cells spread away from the primary tumor, they often follow the trajectories of lymphatic vessels, nerves, white matter tracts, or other heterogeneous structures in tissues.  However, most of the research on cell migration is performed on flat surfaces, ignoring the mechanical confinement that cells experience along these preferred routes of invasion.  ► View lung cancer cells on a flat surface. To study the role of mechanical guides during cancer cell invasion, MGH investigators pioneered the use of microfluidic devices that mechanically constrain migrating cancer cells inside microchannels with a cross-section comparable to cell size.  The investigators observed unexpectedly fast and persistent movement in one direction for several hours.  ► View a summary of 6 hours from a MDA breast cancer cell line migration through 600 microns long channels.  The first cell completes the run in slightly less than 3 hours, for a top speed of 200 microns per hour. In theory, it could take that cell less than 1 month to reach from the breast to the regional lymph nodes located about 10 centimeters away.  Luckily, not all cancer cells are that invasive.  However, almost every type of cancer cell tested by the investigators displays this behavior and their migration occurs spontaneously, in the absence of external gradients.  Better understanding of and eventually the ability to control the migration of cancer cells along different structures inside tissues could have important clinical implications for the treatment of many invasive cancers.

When cancer cells are more efficient is when they move with mitochondria at the front

During cancer cell invasion, faster moving cancer cells play a dominant role by invading further and metastasizing earlier.  Despite the importance of these outlier cells, the source of heterogeneity in their migratory behavior remains poorly understood.  Recently, MGH investigators began to study the location of mitochondria inside cells moving through small channels.  The investigators found how that anterior localization of mitochondria, in between the nucleus and the leading edge of migrating epithelial cancer cells, correlates with faster migration velocities and increased directional persistence. ► View how cancer cells with mitochondria at the front move more efficiently. The asymmetry of mitochondrial localization along the axis of migration is absent during spontaneous cell migration on two-dimensional surfaces and only occurs in the presence of chemical attractant cues or in conditions of mechanical confinement.

Relevant publications

Wong IY, Javaid S, Wong EA, Perk S, Haber DA, Toner M, et al. Spatiotemporal analyses of malignant epithelial-mesenchymal transitions reveal heterogeneous and hierarchical cell invasion behaviors.  Nature Materials, 2014 (in press)

Yan J, Irimia D. Stochastic variations of migration speed between cells in clonal populations. Technology (Singap World Sci). 2014 Sep;2(3):185-188. PubMed PMID: 25436220; PubMed Central PMCID: PMC4245034

Desai SP, Bhatia SN, Toner M, Irimia D. Mitochondrial localization and the persistent migration of epithelial cancer cells. Biophys J. 2013 May 7;104(9):2077-88. PubMed PMID: 23663851; PubMed Central PMCID: PMC3647149

Scherber C, Aranyosi AJ, Kulemann B, Thayer SP, Toner M, Iliopoulos O, et al. Epithelial cell guidance by self-generated EGF gradients. Integr Biol (Camb). 2012 Mar;4(3):259-69. PubMed PMID: 22314635; PubMed Central PMCID: PMC3440622

Smolen GA, Zhang J, Zubrowski MJ, Edelman EJ, Luo B, Yu M, et al. A genome-wide RNAi screen identifies multiple RSK-dependent regulators of cell migration. Genes Dev. 2010 Dec 1;24(23):2654-65. PubMed PMID: 21062900; PubMed Central PMCID: PMC2994039

Wolfer A, Wittner BS, Irimia D, Flavin RJ, Lupien M, Gunawardane RN, et al. MYC regulation of a “poor-prognosis” metastatic cancer cell state. Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3698-703. PubMed PMID: 20133671; PubMed Central PMCID: PMC2840447

Irimia D, Toner M. Spontaneous migration of cancer cells under conditions of mechanical confinement. Integr Biol (Camb). 2009 Sep;1(8-9):506-12. PubMed PMID: 20023765; PubMed Central PMCID: PMC3763902


Daniel Irimia, M.D., Ph.D.

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andrwkirkCancer cells evade confinement