Abstract SY21-02: Extracellular matrix density, alignment, and tumor progression

Abstract

Abstract An increase in the mammographic density of breast tissue is correlated to a four to six-fold increased risk of developing breast carcinoma, making it the single biggest risk factor for breast carcinoma. Increased breast density is associated with a significant increase in the deposition of ECM components, most notably collagen, which leads to an increase in matrix stiffness. In a mouse model of increased collagen deposition, we find that mammary tumor incidence, invasion, and metastasis increased three-fold. Mammary tumors arising in FAK-/- mammary glands were non-invasive and non-metastatic. Gene expression profiling of these tumors identified a metastasis signature regulated by FAK, and further identify novel mechanisms and signaling pathways governing invasion into collagen matrices. Using state-of-the-art non-linear optical imaging techniques (FLIM and SHG), we have imaged collagen and cells at the tumor-stromal boundary in live, unfixed mammary tumors. We find that during tumor progression, the structure and alignment of collagen fibers is altered, such that the perpendicular realignment of collagen fibers is completely coincident with areas of local invasion. A recent analysis of 207 human samples demonstrates that the presence of perpendicular aligned collagen was a novel significant and independent prognostic indicator of poor patient survival, with a risk factor of 4.3. To determine whether fibril alignment facilitates invasion, we engineered aligned matrices, and found that human breast carcinoma cells preferentially invaded along perpendicularly aligned vs. random or parallel collagen fibers. Our results demonstrate collagen fibers serve as a highway to facilitate local invasion, and promote distal metastasis. Citation Format: Patricia J. Keely. Extracellular matrix density, alignment, and tumor progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY21-02. doi:10.1158/1538-7445.AM2014-SY21-02