Force and Malignant Transformation

L KASS; K R JOHNSON; N ZAHIR; J N LAKINS; D GASSER; V M WEAVER

San Diego, California, USA

Congreso; American Society of Cell Biology 46th Annual Meeting; 2006

American Society of Cell Biology

Stromal-epithelial interactions regulate tissue homeostasis and are altered in tumors, and modifying extracellular matrix-integrin interactions can profoundly influence expression of the malignant phenotype in culture and in vivo. However, the molecular mechanisms whereby altered stromal-epithelial interactions regulate tumorigenesis are not well defined. We found that malignant transformation is associated with a significant increase in mammary gland stiffness and mature focal adhesions. We showed that matrix stiffness and/or exogenous force independently induce cell contractility to promote focal adhesion maturation and enhance integrin-dependent signaling to compromise multi-cellular tissue morphogenesis and promote a tumor-like behavior in mammary tissues. Because force-dependent integrin aggregation preceded FA assembly, we generated â1 integrin mutants with increased transmembrane molecular associations (V737N, G744N) and used these mutants to show that forcing focal adhesion maturation increased integrin/growth factor-dependent signaling that compromised multi-cellular tissue morphogenesis and promoted tumorigenic behavior. We now report that force-dependent focal adhesion maturation drives tumorigenic behavior by enhancing cell survival, disrupting cell-cell junctional integrity and promoting growth factor-dependent cell invasion in nonmalignant mammary tissue-like structures within 3D hydrogels. We also found that forcing focal adhesion maturation through ectopic â1 integrin (V737N) expression in pre-malignant MCF10DCIS.com MECs promotes their malignant transformation in 3D rBM culture and in vivo. Results showed that xenografts of pre-neoplastic MCF10DCIS MECs with increased numbers of mature focal adhesions formed larger palpable tumor masses of significantly increased mass as compared to their DCIS controls. Histologically forced focal adhesion maturation promoted malignant transformation evidenced by tumor invasion, increased angiogenesis and enhanced tumor cell survival. Studies are currently underway to explore effects on tumor metastasis and to delineate molecular mechanisms for these effects. (Supp: NIH T32HL00795404 to KRJ; DOD W81XWH-05-1-330 and NIH CA078731 to VMW).