Multiscale Modeling of ECM-tumor interactions in Breast Cancer

描述（由申请人提供）：在人类中，发生浸润性乳腺癌的常见风险因素是乳腺X线摄影检测到的致密乳腺组织。这种致密组织与基质胶原蛋白增加、上皮细胞增加和脂肪组织减少有关。最近在转基因小鼠中的研究表明，乳腺间质组织中胶原密度的增加在促进乳腺肿瘤的形成和侵袭性方面起着致病作用。其他研究暗示细胞外基质（ECM）沉积和/或交联下游的组织刚性促进侵略性，侵入性细胞表型。相反，正常上皮细胞和原位癌上皮细胞的基底膜ECM蛋白被认为抑制肿瘤进展。由于细胞外基质与肿瘤细胞相互作用的复杂性，使用传统的生物学方法很难完全分离和理解细胞外基质对肿瘤进展的各种影响。因此，我们建议使用跨学科的方法，我们开发了一个三维的基于细胞的多尺度ECM-乳腺癌相互作用的数学模型。使用该模型，我们将进行计算机模拟实验，以检验ECM刚性和基质胶原纤维化提供促进肿瘤进展和侵袭的环境的总体假设。我们将专门测试胶原纤维密度、宽度、排列和交联的作用，以及基底膜ECM和蛋白酶对癌症生长和侵袭的作用。所有建模将与实验完全集成，以获得真实的参数和单独的测试预测。我们预计，该项目将确定促进乳腺癌进展的关键微环境因素，并为未来的治疗干预奠定基础。

DESCRIPTION (provided by applicant): In humans, a common risk factor for the development of invasive breast cancer is dense breast tissue, detected by mammography. This dense tissue is associated with increased stromal collagen, increased epithelial cells, and decreased fatty tissue. Recent studies in transgenic mice indicate that increased collagen density in breast stromal tissue plays a causative role in promoting both the formation and invasiveness of breast tumors. Additional studies implicate tissue rigidity downstream of extracellular matrix (ECM) deposition and/or cross linking in promoting aggressive, invasive cellular phenotypes. Conversely, basement membrane ECM proteins that underlie normal and carcinoma in situ epithelial cells are thought to inhibit tumor progression. Because of the complexity of extracellular matrix-tumor cell interactions, it is difficult to fully isolate and understand the various effects of extracellular matrix on tumor progression using traditional biological approaches. We therefore propose to use an interdisciplinary approach in which we develop a 3-dimensional cell-based multiscale mathematical model of ECM-breast cancer interactions. Using this model, we will perform in silico experiments to test the overall hypothesis that ECM rigidity and stromal collagen fibrosis provide an environment that promotes tumor progression and invasion. We will specifically test the role of collagen fibril density, width, alignment, and crosslinking and the role of basement membrane ECM and proteases on cancer growth and invasion. All modeling will be fully integrated with experimentation to obtain realistic parameters and separately test predictions. We anticipate that this project will identify critical microenvironmental factors promoting breast cancer progression and lay the groundwork for future therapeutic intervention.