The goal of this project is to understand how cell interactions with their microenvironment regulate DNA repair. The cell microenvironment is composed of the extracellular matrix (ECM), a mesh-like scaffolding of proteins with soluble factors such as hormones and cytokines.
We focus on breast cancer risk conferred by obesity, a condition where soluble factors and the physical properties of the ECM (stiffness in particular) are altered. This project relies on analyses of human breast tissue, mouse models, and 3D breast epithelial organoids produced in 3D culture.
We and others have shown that epithelial polarity, defining the architecture of the normal epithelium, is necessary for efficient DNA repair (Vidi et al., J Cell Sci, 2012). Mechanistically, the ECM is linked to the cell nucleus by a continuum of structural elements; we found that localization of the nucleoskeletal protein NuMA depends on cell-ECM interaction via integrins and discovered novel functions for NuMA in DNA repair (Vidi et al., NAR, 2014; Salvador-Moreno et al., NAR, in revision).
In obesity, the adipokine leptin is often found at higher levels systemically and in the breast. We identified that leptin induces loss of epithelial cell polarity (Tenvooren et al., Oncogene, 2019) and are now focusing on the relationship between obesity and the DNA damage response.
NCI K99/R00 (2012-2018)
Vera Bradley Foundation (2017-2019)
DoD BCRP Breakthrough Award (2018-2021)
Connexin 43 maintains tissue polarity and regulates mitotic spindle orientation in the breast epithelium. Bazzoun D, Adissu HA, Wang L, Urazaev A, Tenvooren I, Fostok SF, Chittiboyina S, Sturgis J, Hodges K, Chandramouly G, Vidi PA, Talhouk RS, Lelièvre SA. J Cell Sci. 2019 Apr 16.
The nuclear structural protein NuMA is a negative regulator of 53BP1 in DNA double-strand break repair. Salvador Moreno N, Liu J, Haas KM, Parker LL, Chakraborty C, Kron SJ, Hodges K, Miller LD, Robinson PL, Lelièvre SA, and Vidi PA. Nucleic Acids Res. 2019 Apr 8;47(6):2703-2715. Breakthrough NAR article
Elevated leptin disrupts epithelial polarity and promotes premalignant alterations in the mammary gland. Tenvooren I, Jenks MZ, Rashid H, Cook KL, Muhlemann JK, Sistrunk C, Holmes J, Wang K, Bonin K, Hodges K, Lo HW, Shaikh A, Ignacio G. Camarillo IG, Lelièvre SA, Seewaldt V, Vidi PA. Oncogene. 2019 Jan. 22.
High-content image informatics of the structural nuclear protein NuMA parses trajectories for stem/progenitor cell lineages and oncogenic transformation. Vega SL, Liu E, Arvind V, Bushman J, Sung HJ, Becker ML, Lelièvre S, Kohn J, Vidi PA, Moghe PV. Exp Cell Res. 2017 02 01; 351(1):11-23.
NuMA promotes homologous recombination repair by regulating the accumulation of the ISWI ATPase SNF2h at DNA breaks. Vidi PA, Liu J, Salles D, Jayaraman S, Dorfman G, Gray M, Abad P, Moghe PV, Irudayaraj JM, Wiesmüller L, Lelièvre SA. Nucleic Acids Res. 2014 Jun; 42(10):6365-79.
Interconnected contribution of tissue morphogenesis and the nuclear protein NuMA to the DNA damage response. Vidi PA, Chandramouly G, Gray M, Wang L, Liu E, Kim JJ, Roukos V, Bissell MJ, Moghe PV, Lelièvre SA. J Cell Sci. 2012 Jan 15; 125(Pt 2):350-61.