Cellular and Molecular Bioengineering

, Volume 12, Issue 5, pp 455–480 | Cite as

Tumor Cell Mechanosensing During Incorporation into the Brain Microvascular Endothelium

  • Marina A. Pranda
  • Kelsey M. Gray
  • Ariana Joy L. DeCastro
  • Gregory M. Dawson
  • Jae W. Jung
  • Kimberly M. StrokaEmail author



Tumor metastasis to the brain occurs in approximately 20% of all cancer cases and often occurs due to tumor cells crossing the blood-brain barrier (BBB). The brain microenvironment is comprised of a soft hyaluronic acid (HA)-rich extracellular matrix with an elastic modulus of 0.1–1 kPa, whose crosslinking is often altered in disease states.


To explore the effects of HA crosslinking on breast tumor cell migration, we developed a biomimetic model of the human brain endothelium, consisting of brain microvascular endothelial cell (HBMEC) monolayers on HA and gelatin (HA/gelatin) films with different degrees of crosslinking, as established by varying the concentration of the crosslinker Extralink.

Results and Discussion

Metastatic breast tumor cell migration speed, diffusion coefficient, spreading area, and aspect ratio increased with decreasing HA crosslinking, a mechanosensing trend that correlated with tumor cell actin organization but not CD44 expression. Meanwhile, breast tumor cell incorporation into endothelial monolayers was independent of HA crosslinking density, suggesting that alterations in HA crosslinking density affect tumor cells only after they exit the vasculature. Tumor cells appeared to exploit both the paracellular and transcellular routes of trans-endothelial migration. Quantitative phenotyping of HBMEC junctions via a novel Python software revealed a VEGF-dependent decrease in punctate VE-cadherin junctions and an increase in continuous and perpendicular junctions when HBMECs were treated with tumor cell-secreted factors.


Overall, our quantitative results suggest that a combination of biochemical and physical factors promote tumor cell migration through the BBB.


Breast cancer Hyaluronic acid Tight junctions Microvasculature 



Atomic force microscopy


Analysis of variance


Aspect ratio


Blood-brain barrier


Bovine serum albumin


Dulbecco’s modified eagle’s medium


Dimethyl sulfoxide


Endothelial cell growth supplement


Extracellular matrix


Fetal bovine serum


Green fluorescent protein


Hyaluronic acid


Human brain microvascular endothelial cell


Junction Analyzer Program


Lysyl oxidase


Phosphate buffered saline


Roswell Park Memorial Institute


Short tandem repeat


Tumor conditioned media


Tight junctions


Vascular endothelial cadherin


Vascular Endothelial Growth Factor


Zonula occludens-1



We thank Dr. Toshiyuki Yoneda for generously providing MDA-MB-231-BR cells. The University of Maryland Computer, Mathematical, and Natural Sciences imaging incubator is acknowledged for providing training and equipment for confocal imaging. Kyle Thomas at Yellow Basket, LLC ( is acknowledged for the JAnaP software development support. We also acknowledge Mary Doolin for help with editing custom Matlab code. We thank Dr. William Luscinskas from the Harvard Medical School for generously providing us with the VE-cadherin-GFP adenovirus.


Funding was provided by Burroughs Wellcome Fund (Career Award at the Scientific Interface). Additional funding was provided by the Ann G. Wylie Dissertation Fellowship from the University of Maryland Graduate School (to MAP), the Fischell Fellowship in Biomedical Engineering (to KMG), the Dr. Mabel S. Spencer Award for Excellence in Graduate Achievement (to KMG), the Clark Doctoral Fellowship (to AJD), the Fischell Department of Bioengineering, and the University of Maryland.

Author Contributions

KMS, MAP, and KMG designed the research. MAP and GMD performed experiments for Fig. 1. GMD analyzed all data for Fig. 1. AJLD performed all experiments and data analysis for Fig. 2, with guidance from MAP. MAP performed confocal microscopy for Fig. 3. KMG performed experiments and analysis for Figs. 4, 5, 6, S2, S3, and S4, with help in analysis from JWJ. KMG prepared Fig. S1. MAP performed experiments and analysis for Figs. 7a–7e. AJLD performed experiments for Figs. 7f–7h, with guidance from MAP, and MAP analyzed data for Figs. 7f–7h. MAP performed confocal microscopy for Fig. 8. MAP and AJLD performed experiments for Fig. 9. MAP performed experiments and all analysis for Fig. 10. MAP performed statistical analysis for Figs. 1, 2, 7, and 10. MAP formatted Figs. 1, 2, 3, 7, 8, 9, and 10. KMG performed statistical analysis and/or formatting for Figs. 4, 5, 6, S2, S3, and S4. MAP, KMG, and KMS wrote the manuscript. All authors edited the manuscript, and all authors reviewed and approved final version of the manuscript.

Conflict of interest

MAP, KMG, GMD, AJLD, JWJ, and KMS declare that they have no conflict of interest.

Human Studies

No human studies were carried out by the authors for this article.

Animal Studies

No animal studies were carried out by the authors for this article.

Supplementary material

12195_2019_591_MOESM1_ESM.pdf (336 kb)
Supplementary material 1 (PDF 336 kb)


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Copyright information

© Biomedical Engineering Society 2019

Authors and Affiliations

  1. 1.Fischell Department of BioengineeringUniversity of Maryland, College ParkCollege ParkUSA
  2. 2.Department of BiologyUniversity of Maryland, College ParkCollege ParkUSA
  3. 3.Biophysics ProgramUniversity of Maryland, College ParkCollege ParkUSA
  4. 4.Center for Stem Cell Biology and Regenerative MedicineUniversity of Maryland – BaltimoreBaltimoreUSA
  5. 5.Marlene and Stewart Greenebaum Comprehensive Cancer CenterUniversity of Maryland – BaltimoreBaltimoreUSA
  6. 6.Fischell Department of BioengineeringUniversity of Maryland, College ParkCollege ParkUSA

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