Densified fibrotic environments are commonly observed in aggressive solid tumors. The mechanisms and origins of these environments are not well understood despite their clinical relevance. Here, we take an integrated computational and experimental approach to decipher the mechanical mechanisms that lead to plastic, irreversible extracellular matrix (ECM) densification in the vicinity of tumors. We emphasize on the impact of dynamic cellular events, particularly dynamic local force generation, on ECM fiber kinetics that leads to spatiotemporal remodeling of the ECM network. We will perform high resolution time lapse imaging to quantitatively capture the force-induced densification of the ECM near tumor clusters, and we will perform computational simulations of dynamic 3D ECM networks to uncover mechanistic insights that govern this phenomenon. Finally, quantitatively guided by our computational and experimental findings, we will develop a novel drug delivery strategy that selectively targets the dynamic mechanical landscape of the tumor microenvironment.

Public Health Relevance

Current cancer therapies are often hindered by the tumor microenvironment. Our study aims to uncover the mechanical mechanisms by which aggressive tumor cells assemble distinct, highly dense fibrotic surroundings and to develop a therapeutic strategy that selectively targets this phenomenon.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21EB026630-03
Application #
9948675
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Rampulla, David
Project Start
2018-09-06
Project End
2021-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Yale University
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520