New research from a group of Vanderbilt biomedical engineers reveals that while cancer cells move quickly in metastasis, they’re rather lazy in which paths they choose.
According to the researchers, migrating cancer cells decide which path in the body to travel based on how much energy it takes, opting to move through wider, easier to navigate spaces rather than smaller, confined spaces to reduce energy requirements during movement.
These findings suggest energy expenditure and metabolism are significant factors within metastatic migration, which lends credence to recent clinical interest in the study of metabolomics and the targeting of cellular metabolism as a way to prevent metastasis.
The discoveries appear in a new paper, “Energetic costs regulated by cell mechanics and confinement are predictive of migration path during decision-making,” published today in the journal Nature Communications.
Led by Cynthia Reinhart-King, Cornelius Vanderbilt Professor of Engineering, the research is the first study to quantify the energetic costs of cancer cells during metastasis – enabling the prediction of specific migration pathways.
These new findings build on similar research from the Reinhart-King Lab, published earlier this year, which discovered “drafting” techniques used by cancer cells to conserve energy during migration.
“These cells are lazy. They want to move, but they will find the easiest way to do it,” noted Reinhart-King. “By manipulating many different variables, we were able to track and build predictions of cellular preference for these paths of least resistance in the body based on how much energy a cell would need to move.”
Lead author on the paper, graduate student Matthew Zanotelli, used a variety of methods to test and map out cellular movement, including tracking cells through a constructed maze of pathways as they manipulated the mechanical properties of each cancer cell, and even the physical properties of the paths themselves.
While the scope of the new research focuses on metastatic cancer cells, Zanotelli noted that the results of this study could soon have broader implications for a variety of situations beyond cancer.
“This type of cellular movement happens in other instances – for example, during inflammation and around healing wounds,” said Zanotelli. “We’re excited to have this initial understanding of energy and cell migration and hope it will prove foundational for future, broader research.”
Cell migration is a critical aspect of the invasion-metastasis cascade and is significantly influenced by the microenvironment. The physical properties of the extracellular matrix (ECM) have been identified as key mediators of cell behavior and determine requirements for motility1,2,3.
During cancer progression, the ECM commonly becomes deregulated and disorganized4 resulting in a highly heterogeneous ECM containing restricting pores, cross-sectional areas, and channel-like tracks5.
These tight interstitial spaces can range from ~3 to 30 μm in width2, creating complex topographies that present directional choices to migrating cells5,6,7.
Notably, channel-like tracks in the matrix, which are native to the ECM or prepatterned by cells themselves using metalloproteinases (MMPs), provide physical guidance, and offer a path of least resistance for migrating cells2,8,9.
Once channel-like tracks are created by “leading” cancer cells, other “following” cancer cells utilize these microtracks to rapidly disseminate in an unimpeded, MMP-independent manner10.
This mode of migration may explain the limited clinical success of MMP inhibitors to treat metastasis11.
As these microtracks in the matrix provide strong proinvasive cues to tumor cells, understanding the mechanisms of cancer cell motility through physiologically relevant confining tracks will be critical to developing therapeutic strategies to target metastasis.
To navigate these physical barriers and migrate, cells dynamically coordinate cellular machinery to generate forces and remodel their cytoskeleton and/or the surrounding matrix12,13,14, both of which are energy-demanding processes15,16,17.
Cells generally meet such energy needs through the dephosphorylation of ATP into ADP. Maintaining an adequate supply of ATP is critical for cellular remodeling18, and ATP production is determined by fluctuating energetic demands of the cell19,20.
Our recent work indicates that individual migrating cells tune their energy utilization relative to the structure and mechanics of their microenvironment21, and collectively migrating cells employ relay-like behavior to invade through physically challenging and energy-demanding environments22.
However, the role of cellular energetics in directional decision-making during migration through spatially complex microenvironments is not well understood.
Here, we show that when presented with migration choices of varying confinement, MDA-MB-231 cells preferentially migrate in the direction of least confinement to minimize energetic costs.
Using a computational model and in vitro experiments, we demonstrate that energetic costs for migration through confined spaces are mediated by a balance between cell and matrix compliance and the degree of spatial confinement to direct migration decision-making.
Increased cell stiffness limits cell body deformation and requires cell-induced matrix displacement for migration through narrow spaces.
The cellular work required for matrix displacement drives the energy requirements for migration, and these energetic costs exponentially increase with increasing cell stiffness.
At high degrees of spatial confinement as well as high cell stiffness and/or high matrix stiffness, elevated energetic costs for movement restrict migration into narrower confined spaces. Using this framework, we can accurately predict the probability of migration decisions by calculating the energetic costs between possible migration paths.
Together, these findings provide insight into the role of cellular energetics in migration and demonstrate that energetic costs, in part, determine a cell’s ability to navigate complex environments.
More information: Matthew R. Zanotelli et al. Energetic costs regulated by cell mechanics and confinement are predictive of migration path during decision-making, Nature Communications (2019). DOI: 10.1038/s41467-019-12155-z
Journal information: Nature Communications
Provided by Vanderbilt University
