The role of mechanics in tumor progression and malignancy over the last few decades, various studies have converged upon the idea that the microenvironment is important in the progression of cancer. Specifically, the normal interactions with the microenvironment can suppress tumor formation and growth, while disruption of the normal context can support the progression and metastasis of tumors. More recent studies have suggested that the mechanical properties of the microenvironment plays an important role in this interaction, but the mechanism by which cells sense the mechanics of the environment, and how this interaction is altered in cancer remains unknown. In this project, we will investigate the effect of mechanics of the microenvironment on mammary epithelial cell proliferation, migration, and malignancy in reconstituted three dimensional alginate gel matrices. Precise control over viscoelasticity and legend density is possible with alginate gels, and a technique to precisely measure the number of bonds cells form with the gel has been established. We will probe the effect of matrix elasticity, viscoelasticity, and ligand density on proliferation and migration of the non-malignant mammary epithelial cells, and see how this response changes for pre-malignant and malignant mammary epithelial cells. Then we will develop a technique to measure strains and stresses exerted by the cells on the alginate gels, and use these measurements to elucidate the mechanism by which the cells physically probe their microenvironment. These measurements will also be conducted across cell lines with different malignant phenotypes to determine whether differences in this mechanism are correlated with different sensitivities to the microenvironment. The experiments proposed here will provide general insight into the nature of cancer malignancy as well as the mechanism by which cells sense their mechanical microenvironment. Such insight could be relevant for diagnosis of cancer malignancy, and suggest new techniques for suppressing tumor progression and malignancy.

Public Health Relevance

The role of mechanics in tumor progression and malignancy Recent studies that have suggested that the environment around cancer cells, and specifically how soft or stiff it is, can affect the growth and malignancy of cancer, but the exact relationship between these variables and how cancer cells feel their environment remains unknown. In this project, we will elucidate this relationship for breast cancer cells, determine how breast cancer cells feel their environment, and investigate how this interaction is altered in malignant cell lines.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F15-D (20))
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Jakowlew, Sonia B
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Harvard University
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Chaudhuri, Ovijit; Gu, Luo; Klumpers, Darinka et al. (2016) Hydrogels with tunable stress relaxation regulate stem cell fate and activity. Nat Mater 15:326-34
Chaudhuri, Ovijit; Gu, Luo; Darnell, Max et al. (2015) Substrate stress relaxation regulates cell spreading. Nat Commun 6:6364
Chaudhuri, Ovijit; Koshy, Sandeep T; Branco da Cunha, Cristiana et al. (2014) Extracellular matrix stiffness and composition jointly regulate the induction of malignant phenotypes in mammary epithelium. Nat Mater 13:970-8