Thursday, June 13, 2019
Therapeutics targeting the PI3K (phosphatidylinositol 3-kinase) and the Ras/MAPK (mitogen-activated protein kinases) pathways have potential as non-toxic treatments for triple-negative breast cancer due to their frequent over-activation in several forms of cancer. Interestingly, the PI3K and Ras/MAPK pathways have been shown to incite cancer dormancy behavior individually and tumorigenic behavior in unison when induced in healthy breast epithelial cells (MCF-10A) in vivo. Understanding the mechanical behavior of MCF-10A cells as a function of PI3K and/or Ras/MAPK pathway over-activation further explores the pathways as potential therapeutics and aims to characterize the cross-talk enabling unique dormant/tumorigenic characteristics. Cellular viscoelasticity and adhesion were measured for MCF-10A cells with PTEN (phosphatase and tensin homolog) knockout and activated KRAS (Kristen rat sarcoma viral oncogene homolog) overexpression to activate the PI3K and Ras/MAPK pathways respectively with atomic force microscopy. PTEN knockout alone has no observable influence on cell adhesion but resulted softer cells with less organized cytoskeleton. Activated KRAS overexpression increased cell stiffness and cell adhesion regardless of PTEN expression level. Moreover, the overexpression of activated KRAS enhanced the sensitivity of cells to the substrate stiffness. The findings suggest that the cancer-associated pathways PI3K and Ras/MAPK regulate cell adhesion and mechanics to promote tumor formation and metastasis. More importantly, the results that signify mutations of different molecular pathways associated with cancer dormancy regulate cell mechanics differently suggests that cell stiffness is a biomarker that detects and differentiates different types of dormant cancers.
Qi Wen, Associate Professor, Department of Physics, WPI (Thesis Advisor)
Kristen Billiar, PhD, Professor, Department of Biomedical Engineering, WPI (Chair)
Nancy Burnham, PhD, Professor, Department of Physics, WPI
Kwonmoo Lee, PhD, Assistant Professor, Department of Biomedical Engineering, WPI
Konstantin Balashev, PhD, D.Sc, Faculty, Department of Physical Chemistry, Sofia University
Department of Biomedical Engineering