Abstract 1477: Tumor metastasis is modulated by tissue stiffness in MMTV-PyMT breast cancer model

Abstract

Abstract Tumor metastasis is the major cause of morbidity and mortality from breast cancer, yet there are no effective management strategies and treatments for metastatic breast cancer. These challenges urge us to have a better understanding of tumor metastasis. Factors in the host microenvironment, including stromal cells, cytokines, and non-cellular extracellular matrix (ECM), are known playing important roles on the dynamic process of tumor metastasis. Our and other recent studies have shown breast tumor progression is associated with ECM remodeling, increased collagen cross-linking and tissue stiffening. Tissue stiffening, in particular, promotes tumor cell invasion in MMTV-Her2/Neu mouse model by enhancing the cross talk between the focal adhesion and oncogenic signaling 1. However, ECM is involved in many steps of tumor metastasis, we do not know explicitly if ECM and tissue stiffness would affect the final tumor metastasis, if so how. We answered our questions by investigating the effects of altered tissue stiffness on the lung metastasis in the MMTV-PyMT mouse model for breast cancer as MMTV-PyMT mice develop lung metastasis with 100% efficiency. We inhibited Lysyl oxidase mediated collagen I crosslinking (beta-aminopropion, BAPN 1) in MMTV-PyMT mice at different ages, measured mammary tissue stiffness with high-resolution tissue diagnostic probe, and examined the lung metastasis. We found that there was a close correlation between tissue stiffness and lung metastasis and that preventing tissue stiffening reduced lung metastasis in PyMT model without affecting primary tumor growth. In addition, we found this reduced lung metastasis was correlated with fewer circulating tumor cells. Further studies showed that BAPN inhibited tumors were less hypoxic and that the tumor cells were less migratory than their corresponding controls. These results suggest that increased collagen crosslinking and tissue stiffness contribute to breast tumor metastasis by facilitating tumor cell migration and intravasation processes. A stiffer tissue and ECM not only modulate the capability of tumor cells to migrate but also affect the substrates on which tumor cells migrate. These two major effects of tissue stiffening make tumor cells succeed in intravasation, which is required for their subsequent lung colonization. We are now investigating the underlying molecular and biomechanical mechanisms involved in this specific situation. These studies, together with our previous work on MMTV-Her2/Neu model 1, show that tissue stiffness modulates multiple stages of breast cancer metastasis and will help us to develop novel strategies of managing metastatic breast caners. (Support by DOD.WX81XWH-05-1-0330, NIH/NCI RFA-CA-09-009) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1477. doi:1538-7445.AM2012-1477