Tissue stiffness cooperates with ErbB2 to drive malignant transformation

K R JOHNSON; L KASS; N ZAHIR; D GASSER; A GEFEN; S S MARGULIS; V M WEAVER

Chicago, Illinois, USA

Congreso; Biomedical Engineering Society 2006; 2006

Biomedical Engineering Society

A reactive stroma promotes malignant transformation and induces aggressive behavior of tumors.  We are using MMTV-Her2/neu mice, organotypic mammary epithelial cell (MEC) three-dimensional tissue models, and xenografts to study how alterations in the physical properties of the extracellular matrix (ECM) could modulate mammary tumorigenesis.   Using compression and shear analysis, we show that malignant transformation is preceded by and associated with a progressive stiffening of the tissue.  Biochemical, immunological, and polarization microscopy analysis and organotypic culture modeling indicate that gland stiffness, altered tissue morphology, and tumor invasion are functionally linked to increased collagen deposition, bundling, and crosslinking.  Moreover, studies with MECs that express p75.B2 (ie. an inducible homodimerizing ErbB2) and ribose-induced crosslinked collagen gels demonstrate that ECM stiffness can cooperate with oncogenes to drive breast invasion and transformation.  Matrix force appears to drive breast tumor behavior by enhancing integrin clustering to stabilize integrin adhesions, and forced integrin clustering compromises MEC morphogenesis.  Because we showed that matrix stiffness enhances epidermal growth factor (EGF) receptor-dependent PI3 kinase activity and PI3 kinase enhances tumor invasion, we currently are investigating whether matrix stiffness promotes tumor progression by altering EGFR signaling through PI3 kinase and if so how. (Supp: NIH T32HL00795404 to KRJ; DOD W81XWH-05-1-330 and NIH CA078731 to VMW).