A Biophysico-computational Perspective of Breast Cancer Pathogenesis and Treatment Response
Annual rept. 1 Mar 2005-28 Feb 2006
PENNSYLVANIA UNIV PHILADELPHIA
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Apoptosis regulates the pathogenesis and treatment responsiveness of breast tumors yet the molecular mechanisms whereby breast cancer cells resist apoptosis remains unknown. We found that coincident with malignant transformation and in association with an increase in collagen deposition, cross-linking and reorganization, the mammary gland becomes incrementally stiffer and that the elastic modulus of the tissues to which breast tumor cells characteristically metastasize varies widely. We used natural collagen and basement membrane BM hydrogels as well as synthetic laminin and BM-cross linked polyacrylamide gels with precisely calibrated compliances, and could show that elevated matrix stiffness independently induce mammary cell proliferation, perturb cell-cell integrity, disrupt tissue polarity, and inhibit apoptosis-dependent lumen formation to disrupt mammary tissue morphogenesis When we varied matrix force within the range we measured for the various metastatic and transformed tissues, we could modify the activity of several key stress response pathways previously linked to apoptosis regulation Matrix mediated stress pathway regulation profoundly influenced the apoptosis responsiveness of mammary tissue to a diverse array of exogenous death stimuli including chemotherapeutics such as taxol, immune receptor activators including trail and gamma irradiation Towards delineating a molecular mechanism we were able to demonstrate that matrix stiffness increases the expression and activation of integrins, drives the assembly of mature focal adhesions, and increases Rho GTPase-dependent intracellular contractility. Experiments are now in progress to further explore these findings using novel biomaterials and imaging modalities and organotypic culture manipulations.
- Anatomy and Physiology
- Medicine and Medical Research
- Biomedical Instrumentation and Bioengineering