Angiogenesis is upregulated in solid tumors, but the microvasculature that forms is more tortuous and permeable than typical vasculature. Traditional cancer therapies have focused on inhibiting angiogenesis to starve tumors. However, more recent evidence suggests that this approach may have deleterious effects because minimizing angiogenesis increases hypoxia in the tumor which is associated with decreased efficacy of chemotherapeutic and radiation treatment. Moreover, incomplete or leaky vessels can facilitate the intravasation of metastatic cells into the vasculature. As such, stabilizing vasculature may be a promising therapeutic approach to minimizing metastasis, increasing chemotherapeutic efficacy and improving drug delivery to the tumor. Significant emphasis has been placed on targeting VEGF, as it is known to play a key role in promoting angiogenesis and causing increased vascular permeability. However, anti-VEGF therapeutics has met with limited success in several cancer types, including metastatic breast cancer. The researchers' exciting, new data indicates that matrix stiffness, mimicking the stiffening that occurs during breast tumor progression, causes increased angiogenic outgrowth and increased endothelial monolayer permeability- notably, these are the same endothelial phenotypes that are attributed primarily to the action of VEGF. Moreover, these data indicate that matrix stiffness augments endothelial permeability response to VEGF, suggesting a crosstalk between VEGF and matrix stiffness-mediated signaling. Given these findings, this project will investigate the hypothesis that matrix stiffening contributes to impaired microvascular integrity in tumors by disrupting endothelial cell-cell adhesion, and correspondingly, inhibition of stiffening and/or endothelial cell response to stiffening can minimize impaired vascular integrity. Here, 3D in vitro models of matrix stiffness, in vivo models of tumor stiffening, advanced in vivo imaging techniques and RNA-seq will be used to investigate the mechanism by which matrix stiffness alters microvascular permeability in the tumor microenvironment.
In Aim 1, the synergies between matrix stiffness and VEGF-mediated permeability will be defined.
In Aim 2, the effects of mechanical heterogeneities in the matrix on vessel outgrowth and integrity will be investigated.
In Aim 3, approaches to inhibit stiffness-induced vascular barrier disruption will be explored. Together, this work will lead to the identification of novel therapeutic targets to normalize tumor vasculature.

Public Health Relevance

Increased blood vessel growth is a hallmark of tumor growth; however tumor vessels are more permeable than normal vessels, which can impair drug delivery and can facilitate the entry of metastatic cells into the bloodstream. While this permeability has largely been attributed to chemical factors that are present in the tumor, we have acquired data indicating that mechanical factors play a key role. In this project, we will investigate the mechanism by which the mechanical stiffness of tumors disrupts blood vessels with the goal of identifying new therapeutic targets to prevent increased blood vessel permeability.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL127499-02
Application #
9043946
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Gao, Yunling
Project Start
2015-04-01
Project End
2020-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Cornell University
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
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Bordeleau, Francois; Mason, Brooke N; Lollis, Emmanuel Macklin et al. (2017) Matrix stiffening promotes a tumor vasculature phenotype. Proc Natl Acad Sci U S A 114:492-497
Kohn, Julie C; Chen, Adeline; Cheng, Stephanie et al. (2016) Mechanical heterogeneities in the subendothelial matrix develop with age and decrease with exercise. J Biomech 49:1447-1453
Bordeleau, Francois; Reinhart-King, Cynthia A (2016) Tuning cell migration: contractility as an integrator of intracellular signals from multiple cues. F1000Res 5:
Bordeleau, Francois; Califano, Joseph P; Negrón Abril, Yashira L et al. (2015) Tissue stiffness regulates serine/arginine-rich protein-mediated splicing of the extra domain B-fibronectin isoform in tumors. Proc Natl Acad Sci U S A 112:8314-9
Reinhart-King, Cynthia A; Schmidt, Christine E; Peppas, Nicholas A (2015) The 2015 Young Innovators of Cellular and Molecular Bioengineering. Cell Mol Bioeng 8:305-306